Solid forms of 3-((1r,3r)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2h-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use

ABSTRACT

Provided herein are solid forms, salts, and formulations of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, processes and synthesis thereof, and methods of their use in the treatment of cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional patent application claims the benefit of U.S.Provisional Patent Application No. 62/687,930, filed Jun. 21, 2018, andU.S. Provisional Patent Application No. 62/719,896, filed Aug. 20, 2018,each of which is incorporated herein by reference in its entirety andfor all purposes.

SEQUENCE LISTING

This application incorporates by reference a Sequence Listing submittedwith this application as text file entitled P34807-WO_SL.txt created onJun. 12, 2019 and having a size of 16.4 kilobytes.

FIELD OF THE INVENTION

Provided herein are solid forms of3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol,and methods of their use in the treatment of cancer. Further describedherein are processes for preparing fused tricyclic compounds comprisinga substituted phenyl or pyridinyl moiety.

BACKGROUND

Fused tricyclic compounds comprising a substituted phenyl or pyridinylmoiety within the scope of the present disclosure are useful as estrogenreceptor (“ER”) targeting agents.

The ER is a ligand-activated transcriptional regulatory protein thatmediates induction of a variety of biological effects through itsinteraction with endogenous estrogens. Endogenous estrogens include 17β(beta)-estradiol and estrones. ER has been found to have two isoforms,ER-α (alpha) and ER-β (beta). Estrogens and estrogen receptors areimplicated in a number of diseases or conditions, such as breast cancer,lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrialcancer, uterine cancer, as well as others diseases or conditions. ER-αtargeting agents have particular activity in the setting of metastaticdisease and acquired resistance. ER-α targeting agents are disclosed inU.S. Publication Number 2016/0175289.

Useful processes for preparing fused tricyclic compounds comprising asubstituted phenyl or pyridinyl moiety are disclosed in U.S. PublicationNumber 2016/0175289. However, there is a need for improved processes forpreparing ER-α targeting agents.

There exists significant complexity surrounding the identification andselection of a solid form of a pharmaceutical compound. The differencesin solid forms of such compounds affects both physical and chemicalproperties and may alter the processing, stability, bioavailability,formulation, and storage of pharmaceutical compounds. There is noreliable predictability of the solid form and its usefulness as acrystalline solid or amorphous solid. Crystalline solids may beconsidered useful, for example, for physical or chemical stabilitywhereas amorphous solids may be considered useful, for example, forenhanced dissolution and increased bioavailability.

Mixtures of crystalline materials arises from polymorphism. It is notpossible to predict, a priori, if crystalline forms of a compound exist,much less whether crystalline forms can be prepared or isolated. Joneset al., 2006, Pharmaceutical Cocrystals: An Emerging Approach toPhysical Property Enhancement,” MRS Bulletin 31:875-879 (At present itis not generally possible to computationally predict the number ofobservable polymorphs of even the simplest molecules). The number ofpossible solid forms results in differing chemical and physicalproperties for a pharmaceutical compound and can greatly affectdevelopment, stability, and marketing of the product.

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 17β (beta)-estradiol and estrones. ER has been foundto have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens andestrogen receptors are implicated in a number of diseases or conditions,such as breast cancer, lung cancer, ovarian cancer, colon cancer,prostate cancer, endometrial cancer, uterine cancer, as well as othersdiseases or conditions. There is a need for new ER-α targeting agentsthat have activity in the setting of metastatic disease and acquiredresistance. Accordingly, there remains a need for cancer therapieshaving particular solid forms.

SUMMARY

Provided herein are solutions to the problems above and other problemsin the art.

In one aspect provided herein is a compound, Compound B, having the name3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-oltartrate, as described herein.

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern comprising peaks at 19.32, 20.26,21.63, 23.28, or 24.81±0.1° 2θ (+0.1°2θ).

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern comprising peaks at 11.49, 12.54,19.16, 19.42, or 24.67±0.1° 2θ (+0.1° 2θ).

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern substantially as shown in FIG. 10 orFIG. 14.

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern comprising peaks at 11.31, 15.70,16.54, 19.10, or 22.76±0.1° 2θ.

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern comprising peaks at 12.52, 15.90,19.66, 20.65, or 24.99±0.1° 2θ.

In another aspect provided herein is a crystal form of Compound B havingan X-ray powder diffraction pattern comprising peaks at 11.46, 12.51,19.29, 19.42, or 20.23±0.1° 2θ.

In another aspect provided herein is an amorphous solid comprisingCompound A.

Further provided herein are pharmaceutical compositions comprisingCompound B or a crystal salt thereof. Such compounds and pharmaceuticalcompositions can be used in methods of treating cancer as set forthherein.

In another aspect provided herein is a process for preparing a compoundof formula (IV) or a salt thereof as set forth herein. The processcomprises (1) reacting a reaction mixture comprising a compound offormula (I) as described herein, an organic solvent and thionyl chlorideto form a compound of formula (IIa) as described herein and (2) reactinga reaction mixture comprising the compound of formula (IIa), a catalyst,an oxidant and a solvent to form a compound of formula (II) as describedherein. The process further comprises reacting a reaction mixturecomprising the compound of formula (II) and a compound of formula (III)as described herein in an organic solvent to form a compound of formula(IV) or a salt thereof as described herein.

In another aspect provided herein is a process for preparing a compoundof formula (VIII) or a pharmaceutically acceptable salt thereof asdescribed herein. The process comprises reacting a reaction mixturecomprising a compound of formula (IV) as described herein, a compound offormula (V) as described herein or a compound of formula (X) asdescribed herein, and an organic solvent to form a compound of formula(VI) as described herein. The process further comprises reacting areaction mixture comprising the compound of formula (VI), an organicsolvent, and a compound of formula (VII) as described herein or a saltthereof to form a compound of formula (VIII) or a salt thereof.

In another aspect provided herein is a process for preparing a compoundof formula (VIII) or a pharmaceutically acceptable salt thereof asdescribed herein. The process comprises reacting a reaction mixturecomprising a compound of formula (IX) as described herein or a compoundof formula (X) as described herein, a compound of formula (IV) asdescribed herein and an organic solvent to form the compound of formula(VIII) or a salt thereof as described herein.

In still another aspect provided herein is a process for preparing acompound of formula (IX) or a salt thereof as described herein. Theprocess comprises reacting a reaction mixture comprising a compound offormula (X) as described herein, a compound of formula (VII), or a saltthereof, as described herein an organic solvent and a catalyst to form acompound of formula (XI) or a salt thereof as described herein.

In yet another aspect provided herein is a process for preparing acompound of formula (III) or a salt thereof as described herein. Theprocess comprises reacting a reaction mixture comprising a compound offormula (XII) s described herein, a compound B and an organic solvent toform the compound of formula (XIII) as described herein.

In yet another aspect provided herein is a compound of formula (XVI) asdescribed herein.

Still further provided herein is a process for preparing a compoundhaving formula (XX) is provided, where the process comprises contactinga compound of formula (XXI) as described herein with a proteintransaminase to form a compound of formula (3). The compound of formula(3) is contacted with a compound of formula (II) as described herein toform compound formula (XX).

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the XRPD pattern for Compound B Form A.

FIG. 2A depicts the TGA and FIG. 2B depicts the DSC for Compound B FormA.

FIG. 3 depicts a PLM image for Compound B Form A.

FIG. 4 depicts the XRPD pattern for Compound B Form B.

FIG. 5 depicts the TGA and DSC for Compound B Form B.

FIG. 6 depicts the ¹³C SSNMR for Compound B Form B.

FIG. 7 depicts the ¹⁹F SSNMR for Compound B Form B.

FIG. 8 depicts the water sorption/desorption plot for Compound B Form B.

FIG. 9a depicts the SEM image; FIG. 9b depicts the PLM image forCompound B Form B; FIG. 9c depicts the particle size distribution (PSD)for Compound B Form B.

FIG. 10 depicts a comparative XRPD pattern for Compound B Form C againstForm A and Form B of Compound B. Form C was found to be a mixture ofForm A and Form B.

FIG. 11 depicts the TGA and DSC for Compound B Form C.

FIG. 12 depicts the XRPD pattern for Compound B Form D.

FIG. 13 depicts the TGA and DSC for Compound B Form D.

FIG. 14 depicts the XRPD pattern for Compound B Form E.

FIG. 15 depicts the TGA and DSC for Compound B Form E.

FIG. 16 depicts the XRPD pattern for Compound B Form F.

FIG. 17 depicts the DVS plot for Compound B Form F.

FIG. 18 depicts the DSC for Compound B Form F.

FIG. 19 depicts the XRPD pattern for Compound B Form G.

FIG. 20 depicts the TGA and DSC for Compound B Form G.

FIG. 21 depicts the XRPD pattern overlay for Compound B Form A, Form B,Form C, Form D, Form F, and Form G.

FIG. 22 depicts the XRPD for the compressibility properties for CompoundB Form B.

FIG. 23 depicts the ¹⁹F SSNMR for the compressibility properties forCompound B Form B.

FIG. 24 depicts the DSC for the compressibility properties for CompoundB Form B.

FIG. 25 depicts phase transformation pathways for Compound B Forms A, B,D, and F.

FIG. 26 depicts phase transformation pathways to obtain Compound B FormB from Form F.

FIG. 27a depicts the XRPD pattern for Compound C Form 1; FIG. 27bdepicts the XRPD pattern for Compound C Form 2.

FIG. 28 depicts the TGA and DSC for Compound C Form 1.

FIG. 29 depicts a PLM image for Compound C Form 1.

FIG. 30 depicts the XRPD pattern for Compound D Form M.

FIG. 31 depicts the TGA and DSC for Compound D Form M.

FIG. 32 depicts the XRPD pattern for the amorphous form of Compound A.

FIG. 33 depicts the TGA and DSC for the amorphous form of Compound A.

FIG. 34 depicts cell viability of ER+ breast cancer cell line forCompound B compared to GDC-0810 and GDC-0927.

FIG. 35 depicts effect on tumor volume of Compound B at 0.1 mg/kg and 1mg/kg compared to GDC-0927 at 100 mg/kg.

FIG. 36a depicts CT scanning and FIG. 36b depicts FES-PET scanning of abreast cancer patient treated with Compound B.

FIG. 37a depicts CT scanning and FIG. 37b depicts FES-PET scanning of asecond breast cancer patient treated with Compound B.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by those of ordinary skillin the art to which the invention belongs. See, e.g., Singleton et al.,DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley &Sons (New York, N.Y. 1994); Sambrook et al., MOLECULAR CLONING, ALABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, N.Y.1989). Any methods, devices and materials similar or equivalent to thosedescribed herein can be used in the practice of this invention.

The following definitions are provided to facilitate understanding ofcertain terms used frequently herein and are not meant to limit thescope of the present disclosure. All references referred to herein areincorporated by reference in their entirety.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when referring to doses, amounts, or weight percents ofingredients of a composition or a dosage form, mean a dose, amount, orweight percent that is recognized by one of ordinary skill in the art toprovide a pharmacological effect equivalent to that obtained from thespecified dose, amount, or weight percent. The equivalent dose, amount,or weight percent can be within 30%, 20%, 15%, 10%, 5%, 1%, or less ofthe specified dose, amount, or weight percent.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when referring to a numeric value or range of valuesused for characterization of a particular solid form described herein(e.g., XRPD peak values) indicate that the value or range of values maydeviate from a given value to an extent deemed reasonable to one ofordinary skill in the art while still describing the solid form. In oneembodiment, the value of an XRPD peak position may vary by up to +0.1°2θ (or +0.05 degree 2θ) while still describing the particular XRPD peak.

As used herein, and unless otherwise specified, a crystalline that is“pure,” i.e., substantially free of other crystalline or amorphoussolids or other chemical compounds, and contains less than about 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%,or 0.01% of one or more other solid forms on a weight basis. Thedetection of other solid forms can be accomplished by, for example,diffraction analysis, thermal analysis, elemental combustion analysisand/or spectroscopic analysis. The detection of other chemical compoundscan be accomplished by, for example, mass spectrometry analysis,spectroscopic analysis, thermal analysis, elemental combustion analysisand/or chromatographic analysis.

Unless otherwise specified, the terms “solvate” and “solvated,” as usedherein, refer to a solid form of a substance which contains solvent. Theterms “hydrate” and “hydrated” refer to a solvate wherein the solvent iswater. The terms “solvate” and “solvated,” as used herein, can alsorefer to a solvate of a salt, cocrystal, or molecular complex. The terms“hydrate” and “hydrated,” as used herein, can also refer to a hydrate ofa salt, cocrystal, or molecular complex.

The term “pharmaceutically acceptable,” refers to a diluent, excipient,or carrier in a formulation compatible with the other ingredient(s) ofthe formulation and not deleterious to the recipient thereof.

Compound A refers to the compound having the structure:

and having the name3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol,including a pharmaceutically acceptable salt thereof. Compound A can bea tartaric acid salt as described herein (e.g. Compound B). Compound Acan be a fumaric acid salt as described herein (e.g. Compound C).Compound A can be a malonate salt as described herein (e.g. Compound D).

The term “solid form” refers to a physical form which is notpredominantly in a liquid or a gaseous state. A solid form may be acrystalline form or a mixture thereof. In certain embodiments, a solidform may be a liquid crystal. In certain embodiments, the solid form ofCompound A is Form A, Form B, Form C, Form D, Form E, Form F, Form G,Form 1, or Form 2, an amorphous solid, or a mixture thereof. In oneembodiment, the solid form of Compound A is a tartrate salt. In anotherembodiment, the solid form of Compound A is a fumarate salt or a mixturethereof. A solid form may be a crystal form as defined herein.

The term “crystal form” or “crystalline form” refers to a solid formthat is crystalline. In certain embodiments, a crystal form of acompound described herein may be substantially free of amorphous solidsand/or other crystal forms. In certain embodiments, a crystal form of acompound described herein may contain less than about 1%, less thanabout 2%, less than about 3%, less than about 4%, less than about 5%,less than about 6%, less than about 7%, less than about 8%, less thanabout 9%, less than about 10%, less than about 15%, less than about 20%,less than about 25%, less than about 30%, less than about 35%, less thanabout 40%, less than about 45%, or less than about 50% by weight of oneor more amorphous solids and/or other crystal forms. In certainembodiments, a crystal form described herein is pure. In certainembodiments, a crystal form of a compound described herein may be about99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

The term “amorphous” or “amorphous solid” refers to a solid form thatnot substantially crystalline as determined by X-ray diffraction. Inparticular, the term “amorphous solid” describes a disordered solidform, i.e., a solid form lacking long range crystalline order. Incertain embodiments, an amorphous solid of a compound described hereinmay be substantially free of other amorphous solids and/or crystalforms. In certain embodiments, an amorphous solid may be pure. Incertain embodiments, an amorphous solid of a compound described hereinmay be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure.

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder is a cancer.

The term “effective amount” or “therapeutically effective amount” refersto an amount of a compound described herein capable of treating orpreventing a disorder, disease or condition, or symptoms thereof,disclosed herein.

“Patient” or “subject” is defined herein to include animals, such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys,chickens, turkeys, quails, or guinea pigs and the like, in oneembodiment a mammal, in another embodiment a human. In one embodiment, asubject is a human having or at risk for cancer.

As used herein, the terms “moiety” and “substituent” refer to an atom orgroup of chemically bonded atoms that is attached to another atom ormolecule by one or more chemical bonds thereby forming part of amolecule.

As used herein, the term “alkyl” refers to an aliphatic straight-chainor branched-chain saturated hydrocarbon moiety having 1 to 20 carbonatoms. In particular embodiments the alkyl has 1 to 10 carbon atoms. Inparticular embodiments the alkyl has 1 to 6 carbon atoms. Alkyl groupsmay be optionally substituted independently with one or moresubstituents described herein.

As used herein, the term “substituted” refers to the replacement of atleast one of hydrogen atom of a compound or moiety with anothersubstituent or moiety. Examples of such substituents include, withoutlimitation, halogen, —OH, —CN, oxo, alkoxy, alkyl, alkylene, aryl,heteroaryl, haloalkyl, haloalkoxy, cycloalkyl and heterocycle. Forexample, the term “haloalkyl” refers to the fact that one or morehydrogen atoms of an alkyl (as defined below) is replaced by one or morehalogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl,chloromethyl, etc.). In one embodiment, substituted as used herein canrefer to replacement of at least one hydrogen atom of a compound ormoiety described herein with halogen or alkyl.

As used herein, the term “alkylene” as used herein refers to a linear orbranched saturated divalent hydrocarbon radical of one to twelve carbonatoms, and in another aspect one to six carbon atoms, wherein thealkylene radical may be optionally substituted independently with one ormore substituents described herein. Examples include, but are notlimited to, methylene, ethylene, propylene, 2-methylpropylene,pentylene, and the like.

As used herein, the term “alkoxy” refers to a group of the formula—O—R′, wherein R′ is an alkyl group. Alkoxy groups may be optionallysubstituted independently with one or more substituents describedherein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy,and tert-butoxy.

As used herein, the term “aryl” refers to a cyclic aromatic hydrocarbonmoiety having a mono-, bi- or tricyclic aromatic ring of 5 to 16 carbonring atoms. Bicyclic aryl ring systems include fused bicyclics havingtwo fused five-membered aryl rings (denoted as 5-5), having afive-membered aryl ring and a fused six-membered aryl ring (denoted as5-6 and as 6-5), and having two fused six-membered aryl rings (denotedas 6-6). The aryl group can be optionally substituted as defined herein.Examples of aryl moieties include, but are not limited to, phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and thelike. The term “aryl” also includes partially hydrogenated derivativesof the cyclic aromatic hydrocarbon moiety provided that at least onering of the cyclic aromatic hydrocarbon moiety is aromatic, each beingoptionally substituted.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicmono-, bi- or tricyclic ring system of 5 to 16 ring atoms, comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atomsbeing carbon. In some embodiments, monocyclic heteroaryl rings may be5-6 membered. Bicyclic heteroaryl ring systems include fused bicyclicshaving two fused five-membered heteroaryl rings (denoted as 5-5), havinga five-membered heteroaryl ring and a fused six-membered heteroaryl ring(denoted as 5-6 and 6-5), and having two fused six-membered heteroarylrings (denoted as 6-6). The heteroaryl group can be optionallysubstituted as defined herein. Examples of heteroaryl moieties includepyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl,isothiazolyl, benzothienyl, benzothiophenyl, indolyl, aza-indolyl,isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl,benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl,benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl,thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl,pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl,furopyridazinyl, furopyrimidinyl, and furopyrazinyl.

As used herein, the terms “halo”, “halogen” and “halide”, which may beused interchangeably, refer to a substituent fluorine, chlorine,bromine, or iodine.

As used herein, the term “haloalkyl” refers to an alkyl group whereinone or more of the hydrogen atoms of the alkyl group has been replacedby the same or different halogen atoms, particularly fluorine and/orchlorine atoms. Examples of haloalkyl include monofluoro-, difluoro- ortrifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl ortrifluoromethyl.

As used herein, the term “hydroxyalkyl” refers to an alkyl group whereinone or more of the hydrogen atoms of the alkyl group have been replacedby a hydroxyl moiety. Examples include alcohols and diols

As used herein, the term “heteroalkyl” refers to a straight- orbranched-chain alkyl as defined herein having from 2 to 14 carbons, from2 to 10 carbons, or from 2 to 6 carbons in the chain, one or more ofwhich has been replaced by a heteroatom selected from S, O, P and N.Non-limiting examples of heteroalkyls include alkyl ethers, secondaryand tertiary alkyl amines, amides, and alkyl sulfides.

As used herein, the term “cycloalkyl” means a saturated or partiallyunsaturated carbocyclic moiety having mono-, bi- (including bridgedbicyclic) or tricyclic rings and 3 to 10 carbon atoms in the ring. Thecycloalkyl moiety can optionally be substituted with one or moresubstituents. In particular embodiments cycloalkyl contains from 3 to 8carbon atoms (i.e., (C₃—C₈)cycloalkyl). In other particular embodimentscycloalkyl contains from 3 to 6 carbon atoms (i.e., (C₃-C₆)cycloalkyl).Examples of cycloalkyl moieties include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andpartially unsaturated (cycloalkenyl) derivatives thereof (e.g.cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl,bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, andbicyclo[3.1.1]heptenyl. The cycloalkyl moiety can be attached in a“spirocycloalkyl” fashion such as “spirocyclopropyl”:

As used herein, the terms “heterocycle” or “heterocyclyl” refer to a 4,5, 6 and 7-membered monocyclic, 7, 8, 9 and 10-membered bicyclic(including bridged bicyclic) or 10, 11, 12, 13, 14 and 15-memberedbicyclic heterocyclic moiety that is saturated or partially unsaturated,and has one or more (e.g., 1, 2, 3 or 4 heteroatoms selected fromoxygen, nitrogen and sulfur in the ring with the remaining ring atomsbeing carbon. In some embodiments, the heterocycle is aheterocycloalkyl. In particular embodiments heterocycle or heterocyclylrefers to a 4, 5, 6 or 7-membered heterocycle. When used in reference toa ring atom of a heterocycle, a nitrogen or sulfur may also be in anoxidized form, and a nitrogen may be substituted with one or more(C₁-C₆)alkyl or groups. The heterocycle can be attached to its pendantgroup at any heteroatom or carbon atom that results in a stablestructure. Any of the heterocycle ring atoms can be optionallysubstituted with one or more substituents described herein. Examples ofsuch saturated or partially unsaturated heterocycles include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl. The term the term heterocycle also includes groups inwhich a heterocycle is fused to one or more aryl, heteroaryl, orcycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl,azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl,azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

Unless otherwise indicated, the term “hydrogen” or “hydro” refers to themoiety of a hydrogen atom (—H) and not H₂.

As used herein, the term “organic solvent” refers to any non-aqueouspolar aprotic solvent, polar protic solvent, and non-polar solvent.

As used herein, the term “polar organic solvent” refers to both polaraprotic solvents and polar protic solvents, excluding water.

As used herein, the term “polar aprotic solvent” refers to any polarsolvent not having a proton-donating ability. Examples include, withoutany limitation, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate,propyl acetate (e.g., isopropyl acetate), acetone, dimethylsulfoxide,N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoramide, and propylene carbonate.

As used herein, the term “polar protic solvent” refers to any polarsolvent having a proton-donating ability. Examples include, withoutlimitation, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formicacid, nitromethane and acetic acid. An organic polar protic solventexcludes any effective amount of water.

As used herein, the term “non-polar solvent” refers to solvents thatcontain bonds between atoms with similar electronegativities, such ascarbon and hydrogen, such that the electric charge on the molecule isevenly distributed. Non-polar solvents are characterized as having a lowdielectric constant. Examples include, without limitation, pentane,hexane, heptane, cyclopentane, methyl tert-butyl ether (MTBE), diethylether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroformand dichloromethane (DCM). In some embodiments, the non-polar solventhas a dielectric constant of less than 2, examples of which include,without limitation, pentane, hexane and heptane. As compared to othernon-polar solvents, DCM exhibits some degree of polarity at the bondlevel (i.e., between carbon and chlorine), but only a small degree ofpolarity at the molecular level due to symmetry-based cancellation ofpolarity.

As used herein, the term “anti-solvent” refers to a solvent in which thereferenced compound is poorly soluble and which induces precipitation orcrystallization of said compound from solution.

As used herein, the term “acid catalyst” refers to an acid catalyst suchas, but not limited to, a Brönsted acid, a Lewis acid or aBrönsted-Lowry catalyst. Non-limiting examples of acid catalysts includeacetic acid, glacial acetic acid, trifluoroacetic acid, benzoic acid,pivalic acid, diphenyl phosphoric acid, triflic acid, formic acid,tartaric acid, fumaric acid, malonic acid, salicyclic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid,methanesulfonic acid, camphor sulfonic acid, naphthalene sulfonic acid,clay-based montmorillonite K-10 and resin based amberlyst, andcombinations thereof.

As used herein, the term “amine protecting group” refers to any knownprotecting group that that blocks or protects the functionality ofamines. Amine protecting groups within the scope of the disclosureinclude, without limitation, 1-chloroethyl carbamate (ACD);4-methoxybenzenesulfonamide; acetamide (Ac); benzylamine (Bn); benzyloxycarbamate (CBz); formamide; methyl carbamate; trifluoroacetamide;tert-butoxy carbamate (Boc); p-methoxybenzyl carbonyl (MeOZ);9-fluorenylmethoxycarbonyl (FMOC); bezoyl (Bz); p-methoxybenzyl (PMB);3,4-dimethoxybenzyl (DMPM); p-methoxyphenyl (PMP); Tosyl (Ts); andtrichloroethyl chloroformate (Troc). For a description of amineprotecting groups and their use, see P. G. M. Wuts and T. W. Greene,Greene's Protective Groups in Organic Synthesis 4^(th) edition,Wiley-Interscience, New York, 2006

As used herein, the term “aldehyde protecting group” refers to any knownsubstituent attached to an aldehyde group that blocks or protects thecarbonyl group of the aldehyde functionality. Suitable protecting groupsof the aldehyde functionality include, but are not limited to (a) cyclicacetals and ketals, (b) cyclic mono or di-thio acetals or ketals orother derivatives such as imines, hydrazones, cyanohydrin, oximes orsemicarbazones, for example, dialkyl or diaryl acetals or 1,3 dithiane,(c) cyclic imines such as substituted methylene derivatives orN,N′-dimethylimidazolidine. Some non-limiting examples of aldehydeprotecting groups include 1,3-dithiane, 1,3-dithiolane, diethyl acetal,dimethyl acetal, ethylene glycol acetal, neopentyl glycol acetal,trimethylsilyl cyanohydrin, and trialkyl orthoformates such as triethylorthoformate. For a description of aldehyde protecting groups and theiruse, see, Wuts and Greene.

As used herein, “leaving group” refers to an atom or a group of atomsthat is displaced in a chemical reaction as stable species. Suitableleaving groups are well known in the art, e.g., see, March's AdvancedOrganic Chemistry, 5.sup.th Ed., Ed.: Smith, M. B. and March, J., JohnWiley & Sons, New York: 2001 and T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991, the entirecontents of each are hereby incorporated by reference. Such leavinggroups include, but are not limited to, halogen, alkoxy, sulphonyloxy,optionally substituted alkylsulphonyl, optionally substitutedalkenylsulfonyl, optionally substituted arylsulfonyl, and diazoniummoieties. Examples of some leaving groups include chloro, iodo, bromo,fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl(nosyl), and bromo-phenylsulfonyl (brosyl).

“Transition metal catalysts” within the scope of the disclosure include,without limitation, palladium, platinum, gold, ruthenium, rhodium, andiridium catalysts. Non-limiting examples of suitable catalysts include:(2-Biphenyl)di-tert-butylphosphine gold(I) chloride (“JohnPhos”),2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl gold(I) chloride(“XPhos AuCl”), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylgold(I) bis(trifluoromethanesulfonyl)imide (“XPhos AuNTf2”),Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)(“XPhos Palladacycle”),Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)-methyl-t-butyl ether adduct(“SPhos Palladacycle”), t-BuXPhos palladium(II) phenethylamine chloride(“tBuXPhos Pd GI”),Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(“Xphos Pd G2”),Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(“SPhos Pd G2”),Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(“RuPhos Pd G2”),Chloro[(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(“CPhos-Pd-G2”),[(2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (“CPhos-Pd-G3”),[(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate(“tBuXPhos-Pd-G3”),(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (“RuPhos-Pd-G3”),(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (“XPhos-Pd-G3”),[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (“BrettPhos-Pd-G3”),[(2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphine-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (“JackiePhos-Pd-G3”), tert-butyl BrettPhos-Pd-G3,[tert-butyl BrettPhos-Pd (allyl)]OTf), and combinations thereof.

As used herein, “inorganic acids” refer to acids such as, but notlimited to, hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid,and combinations thereof.

As used herein, “organic acids” refer to acids such as, but not limitedto: acetic acid; trifluoroacetic acid; phenylacetic acid; propionicacid; stearic acid; lactic acid; ascorbic acid; maleic acid;hydroxymaleic acid; isethionic acid; succinic acid; valeric acid;fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid;salicylic acid; oleic acid; palmitic acid; lauric acid; a pyranosidylacid, such as glucuronic acid or galacturonic acid; an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid; cysteinesulfinic acid; an amino acid, such as aspartic acid, glutaric acid orglutamic acid; an aromatic acid, such as benzoic acid, 2-acetoxybenzoicacid, naphthoic acid, or cinnamic acid; a sulfonic acid, such aslaurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,benzenesulfonic acid or ethanesulfonic acid; cysteine sulfonic acid; andcombinations thereof.

As used herein, “inorganic bases” refer to bases such as, but notlimited to, sodium hydroxide, potassium hydroxide, lithium hydroxide,ammonium hydroxide, magnesium hydroxide, sodium carbonate, potassiumcarbonate, and combinations thereof.

As used herein, the term “organic base” refers to an organic compoundcontaining one or more nitrogen atoms, and which acts as a base.Examples of organic bases include, but are not limited to, tertiaryamine bases. Examples of organic bases include, but are not limited to,1,8-Diazabicyclo[5.4.0]undec-7-ene (“DBU”), N-methyl-morpholine (NMM),diisopropylethylamine (DIPEA), triethylamine (TEA), a t-butoxide (e.g.,sodium, potassium, calcium or magnesium tert-butoxide).

Compounds of the present disclosure may present in a salt form whichencompasses pharmaceutically acceptable salts and non-pharmaceuticallyacceptable salts. As used herein, the term “pharmaceutically acceptablesalts” refers to those salts which retain the biological effectivenessand properties of the free bases or free acids, which are notbiologically or otherwise undesirable. In addition to pharmaceuticallyacceptable salts, the compounds of the present disclosure may be in theform of non-pharmaceutically acceptable salts which can be useful as anintermediate for isolating or purifying said compounds.

Exemplary acid salts of the compounds of the present disclosure include,but are not limited, to sulfate, citrate, acetate, oxalate, chloride,bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

Exemplary base salts of the compounds of the present disclosure include,but are not limited to, inorganic salts formed from sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum cations. Organic salts formed from cations including primary,secondary, and tertiary amines; substituted amines including naturallyoccurring substituted amines; cyclic amines; basic ion exchange resins;isopropylamine; trimethylamine; diethylamine; trimethylamine;tripropylamine; ethanolamine; 2-diethylaminoethanol; trimethamine;dicyclohexylamine; lysine; arginine; histidine; caffeine; procaine;hydrabamine; choline; betaine; ethylenediamine; glucosamine;methylglucamine; theobromine; purines; piperazine; piperidine;N-ethylpiperidine; and polyamine resins.

The compounds of the present disclosure can also be solvated, i.e.hydrated. The solvation can be effected in the course of themanufacturing process or can take place i.e. as a consequence ofhygroscopic properties of an initially anhydrous compounds. As herein,“solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Non-limiting examples ofsolvents that form solvates include, but are not limited to, water,isopropanol, ethanol, methanol, DMSO, ethyl acetate (EtOAc), acetic acid(AcOH), and ethanolamine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−) isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”. Incertain embodiments the compound is enriched by at least about 90% byweight with a single diastereomer or enantiomer. In other embodimentsthe compound is enriched by at least about 95%, 98%, or 99% by weightwith a single diastereomer or enantiomer.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,regioisomers and individual isomers (e.g., separate enantiomers) are allintended to be encompassed within the scope of the present disclosure.

The compounds of the invention may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention,including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. In some instances, the stereochemistryhas not been determined or has been provisionally assigned. Many organiccompounds exist in optically active forms, i.e., they have the abilityto rotate the plane of plane polarized light. In describing an opticallyactive compound, the prefixes D and L, or R and S, are used to denotethe absolute configuration of the molecule about its chiral center(s).The prefixes d and 1 or (+) and (−) are employed to designate the signof rotation of plane-polarized light by the compound, with (−) or 1meaning that the compound is levorotatory. A compound prefixed with (+)or d is dextrorotatory. For a given chemical structure, thesestereoisomers are identical except that they are mirror images of oneanother. A specific stereoisomer may also be referred to as anenantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity. Enantiomers maybe separated from a racemic mixture by a chiral separation method, suchas supercritical fluid chromatography (SFC). Assignment of configurationat chiral centers in separated enantiomers may be tentative whilestereochemistry is definitively established, such as from x-raycrystallographic data.

As used herein, “essentially” refers to at least 90%, at least 95%, atleast 98% or at least 99%.

In the description herein, if there is a discrepancy between a depictedstructure and a name given to that structure, then the depictedstructure controls. Additionally, if the stereochemistry of a structureor a portion of a structure is not indicated with, for example, boldwedged, or dashed lines, the structure or portion of the structure is tobe interpreted as encompassing all stereoisomers of it. In some cases,however, where more than one chiral center exists, the structures andnames may be represented as single enantiomers to help describe therelative stereochemistry.

Unless otherwise indicated, the terms “a compound of the formula” or “acompound of formula” or “compounds of the formula” or “compounds offormula” refer to any compound selected from the genus of compounds asdefined by the formula (including any pharmaceutically acceptable saltof any such compound if not otherwise noted).

In one aspect provided herein is a process for preparing a compound offormula (IV), or a salt thereof:

where the process comprises the steps:

(a) reacting a reaction mixture comprising a compound of formula (I), anorganic solvent and thionyl chloride to form a compound of formula (IIa)according to step 1 below, and reacting a reaction mixture comprisingthe compound of formula (Ha), a catalyst, an oxidant and a solvent toform a compound of formula (II) according to step 2 below

wherein

each of R^(1a) and R^(1b) is independently hydrogen, halogen, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, —CN, C₃₋₆ cycloalkyl, or C₃₋₆spirocycloalkyl, and

n is an integer of 2 or 3; and

(b) reacting a reaction mixture comprising the compound of formula (II)and a compound of formula (III) in an organic solvent to form a compoundof formula (IV) or a salt thereof according to step 3 below

wherein B is substituted or unsubstituted indolyl, benzofuranyl,benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl,

each of R^(2a) and R^(2b) is independently hydrogen, halogen, —OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, —CN, C₃₋₆cycloalkyl, or C₃₋₆ spirocycloalkyl,

R^(3a) and R^(3b) are independently hydrogen, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, C₃₋₆heterocycloalkyl, phenyl, C₃₋₆ heteroaryl, or C₃₋₆ spirocycloalkyl, and

the asterisk represents a chiral center when R^(3a) and R^(3b) aredifferent.

In one embodiment, B is substituted indolyl, benzofuranyl,benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl.

In another embodiment, B is unsubstituted indolyl, benzofuranyl,benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl.

In one embodiment, B is a substituted or unsubstituted indolyl,benzofuranyl, or benzothiophenyl. In another embodiment, B is a indolyl,benzofuranyl, or benzothiophenyl substituted with one or more halogen orC₁₋₃ alkyl as described herein. In still another embodiment, B is asubstituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, orpyrrolopyrazinyl. In another embodiment, B is a pyrrolopyridazinyl,pyrrolopyrimidinyl, or pyrrolopyrazinyl substituted with one or morehalogen or C₁₋₃ alkyl as described herein. In yet another embodiment, Bis a substituted or unsubstituted indolyl. In one preferred embodiment,B is unsubstituted indolyl. In one embodiment, B is substituted indolyl(e.g. substituted with one or more halogen or C₁₋₃ alkyl as describedherein). In another preferred embodiment, B is substituted indolylcomprising substitution with at least one moiety selected from the groupconsisting of methyl, Cl, and F. In still another embodiment, B is abenzofuranyl or a substituted benzofuranyl comprising substitution withat least one moiety selected from the group comprising methyl, Cl, andFl.

B may suitably be substituted with one or two substituents independentlyselected from the group consisting of fluorine, chlorine, C₁₋₃ alkyl,C₁₋₃ haloalkyl, —CN, —OH, C₁₋₃ alkoxy and C₁₋₃ hydroxyalkyl. In oneembodiment, B is indolyl substituted with halogen (e.g. F or Cl).

In one embodiment, R^(1a) and R^(1b) are each independently hydrogen,halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, —CN, or C₃₋₆cycloalkyl. In another embodiment, R^(1a) and R^(1b) are eachindependently hydrogen, —F, —Cl, —OH, —CN, —CH₃, —CF₃, —CHF₂, —CH₂F, orspirocyclopropyl. In one embodiment, R^(1a) and R^(1b) are independentlyF or hydrogen. In a preferred embodiment, R^(1a) and R^(1b) are eachindependently hydrogen, —F, or —CH₃. In another preferred embodiment,R^(1a) and R^(1b) are each independently hydrogen, —F, or cyclopropyl.In one embodiment, n is 3.

In one embodiment:

is of the formula

R^(2a) and R^(2b) are each independently hydrogen, halogen, —OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁-3 alkoxy, C₁₋₃ hydroxyalkyl, —CN, or C₃₋₆cycloalkyl. In some embodiments, R^(2a) and R^(2b) are each hydrogen. Inone embodiment, R^(1a) and R^(1b) are each independently —F or CH₃ andR^(2a) and R^(2b) are each independently hydrogen. In one embodiment, Bis a indolyl, benzofuranyl, or benzothiophenyl, R^(1a) and R^(1b) areeach independently —F or CH₃, and R^(2a) and R^(2b) are eachindependently hydrogen.

R^(3a) and R^(3b) are each independently hydrogen, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ hydroxyalkyl, —CN, C₃— cycloalkyl, C₃₋₆heterocycloalkyl, phenyl, or C₃₋₆ heteroaryl. In one embodiment, R^(3a)and R^(3b) are each independently hydrogen or —CH₃.

The asterisk in formula (IV) represents a chiral center when R^(3a) andR^(3b) are different. In some embodiments, therefore, R^(3a) and R^(3b)are different and are hydrogen or —CH₃.

In one embodiment, the compound of formula (I) is:

including stereoisomers thereof.

In a particular embodiment, the compound of formula (I) is:

In another embodiment, the compound of formula (I) is:

including stereoisomers thereof.

In one embodiment, the compound of formula (II) is:

including steroisomers thereof.

In a particular embodiment, formula (II) is:

In some particular embodiment, the compound of formula (I) is:

including stereoisomers thereof.

In one embodiment, the compound of formula (III) is:

including stereoisomers thereof, where X is —NH—, —N—C₁-C₃ unsubstitutedalkyl, —O— or —S—.

In a particular embodiment, the compound of formula (III) is:

In another particular embodiment, the compound of formula (III) is:

In one embodiment, the compound of formula (IV) is:

or salt thereof, including stereoisomers thereof; and wherein theasterisk denotes a chiral center.

In a particular embodiment, formula (IV) is:

In another particular embodiment, formula (IV) is:

In a particular embodiment, the compound of formula (I) is:

the compound of formula (II) is

the compound of formula (III) is

andthe compound of formula (IV) is

In step 1, a reaction mixture comprising a compound of formula (I), anorganic solvent and thionyl chloride is reacted to form a compound offormula (IIa). In one embodiment, the compound of formula (I) iscompound 1. In one embodiment, the organic solvent is a non-polarsolvent or a polar solvent. In one embodiment, the solvent is non-polar.Non-limiting examples of suitable non-polar solvents include pentane,cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane,chloroform, diethyl ether, dichloromethane (“DCM”), and combinationsthereof. In one embodiments, the solvent is DCM. In one embodiment, theconcentration of formula (I) in the solvent may suitably be about 25g/L, about 50 g/L, about 100 g/L, about 150 g/L, about 200 g/L, about250 g/L, and up to a concentration approaching saturation at thereaction temperature, and ranges constructed from those concentrations,such as from about 100 g/L to about 250 g/L. The equivalent ratio ofthionyl chloride to the compound of formula (I) is suitably about 1:1,about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1 or about 2:1, andranges constructed from those ratios, such as from about 1.1:1 to about1.5:1. In one embodiment, the reaction temperature is below the reactionmixture reflux temperature. In one embodiment, the reaction is run atreflux. For instance, where the solvent is DCM, the reaction temperaturemay suitably be from about 25° C. to about 40° C. The reaction time isnot narrowly limited and the reaction is typically continued until theconversion of formula (I) to formula (IIa) is essentially complete suchas determined by chromatography (e.g., TLC, GC or HPLC).

Upon reaction completion, the reaction mixture may be quenched. In somesuch embodiments, the reaction mixture may be quenched with cold water.In such embodiments, the phases may be separated into an aqueous phaseand organic phase comprising the compound of formula (IIa). The aqueousphase may be extracted one or more times with organic solvent to recoveradditional compound formula (IIa).

In step 2, a reaction mixture comprising the compound of formula (IIa),a catalyst, an oxidant and a solvent is reacted to form a compound offormula (II). In one embodiment, the organic phase or combined organicphases from step 1, comprising formula (IIa), is used as the source offormula (IIa) for step 2. In one embodiment, the catalyst is a redoxactive metal catalyst. Non-limiting examples of suitable catalystsinclude NiCl₂, RuCl₃, CoCl₂, FeCl₃, FeCl₂, and MnCl₂. Non-limitingexamples of suitable oxidants include NaIO₄, NaOCl, and Oxone. Suitableorganic solvents include non-polar and polar solvents as discussedelsewhere herein. In general, the oxidant is in equivalent excess tocompound formula (Ha), for instance, the ratio of oxidant to compoundformula (IIa) may be 1.1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 or5:1. The step 2 reaction mixture may further comprise water. In suchembodiments, the volume ratio of water to organic solvent used in thestep 1 reaction mixture may be about 9:1, about 5:1, about 3:1, about2:1, about 1:1, about 1:2, about 1:3, about 1:5 or about 1:9, and rangesconstructed therefrom, such from about 2:1 to about 1:2. The step 2reaction temperature may suitably be about 25° C., about 15° C., about5° C., about 0° C., about −5° C. or about −10° C., and rangesconstructed therefrom, such as from about −10° C. to about 10° C. In oneembodiment, the organic phase(s) comprising formula (IIa), catalyst, andwater are combined and cooled to a reaction temperature. The oxidant isthen added over a period of time while maintaining the temperaturearound the reaction temperature.

Upon reaction completion, the step 2 reaction mixture may be separatedinto an aqueous phase and organic phase comprising the compound offormula (II) in solution. In some optional embodiments, the reactionmixture may be filtered, such as through a filter aid (e.g., celite)prior to phase separation. The aqueous phase may be extracted one ormore times with organic solvent to recover additional compound formula(II).

In another embodiment, the step 2 organic phase(s) may be worked up bymethods known to those skilled in the art. For instance, the organicphases may be washed with a base, such as with an aqueous solution ofNa₂SO₃. The organic phases may further optionally be dried, such as witha brine solution and/or by the addition of a solid drying agent such asCaCl₂, MgSO₄ or Na₂SO₄. Solid desiccants may suitably be removed byfiltration. In one embodiment, the compound formula (II) solution may beused for subsequent reaction. In one embodiment, compound formula (II)may be isolated from the solution by methods known in the art such as bydistillation, concentration, precipitation (such as by addition of ananti-solvent or pH adjustment) and/or crystallization. In some suchembodiments, the organic phase(s) may be concentrated by distillation orstripping to reduce the volume, such as by at least 25%, 50%, 100% ormore. Compound formula (II) may then be precipitated/crystallized fromsolution by addition of an anti-solvent followed by optional furtherconcentration. In one embodiment, the anti-solvent is a C₄₋₈ nonionicsolvent such as pentane, hexane or heptane. Compound formula (II) solidsmay be collected by methods known in the art such as filtration orcentrifugation. The solids may be dried, such as under partial vacuum,to yield solid compound formula (II). The yield to compound formula (II)from compound formula (I) for steps 1 and 2 is at least 60%, at least70%, or at least 75%. In one embodiment, the compound of formula (II) iscompound 2.

In step 3, a reaction mixture comprising the compound of formula (II), acompound of formula (III), and an organic solvent is reacted to form acompound of formula (IV). In one embodiment, the organic solvent is apolar aprotic solvent. Non-limiting examples of suitable solventsinclude tetrahydrofuran, ethyl acetate, acetone, dimethylformamide,acetonitrile (“ACN”), dimethyl sulfoxide, nitromethane and propylenecarbonate. In one embodiment, the solvent is ACN. The mole ratio ofcompound formula (II) to compound formula (III) is suitably about 1:1,about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, orgreater, and ranges constructed from those ratios, such as between 1:1and 1.3:1. The concentration of compound formula (II) in the solvent issuitably about 10 g/L, about 25 g/L, about 50 g/L, about 75 g/L, about100 g/L, about 125 g/L, about 150 g/L, and up to a concentrationapproaching saturation at the reaction temperature, and rangesconstructed from those concentrations, such as from about 50 g/L toabout 150 g/L. The acid catalyst may be an acid catalyst as describedelsewhere herein. In some embodiments, the acid catalyst is sulfuricacid, p-toluene sulfonic acid (p-TsOH), or methansulfonic acid, orcombinations thereof. In one embodiment, the acid catalyst is p-toluenesulfonic acid. The equivalent ratio of acid catalyst to compound formula(II) is suitably about 0.75:1, about 0.9:1, about 1:1, about 1.05:1,about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, orgreater, and ranges constructed therefrom, such as from about 1:1 toabout 1.2:1. In one embodiment, the compound of formula (III) iscompound 3.

In some step 3 embodiments, compound formula (II), compound formula(III), the organic solvent and a base are combined to form an admixture.The base may suitably be a moderate base, non-limiting examples of whichinclude potassium tert-butoxide, trimethylamine, sodium bicarbonate,potassium bicarbonate, sodium carbonate, potassium carbonate, sodiumhydroxide, ammonium hydroxide, and combinations thereof. The admixturemay be heated with agitation to a reaction temperature, typically atemperature of from 2° C. to about 30° C. below the reflux temperatureup to the reflux temperature, and held for a time sufficient toessentially complete the formation of a reaction product comprisingcompound formula (III). In the case of ACN solvent, the reactiontemperature is suitably about 65° C., about 70° C., about 75° C., orabout 80° C. The reaction product mixture may then be cooled, such as toless than 50° C., than 40° C., or than 30° C., and optionally filteredto remove solid impurities. The solids may be optionally washed with thesolvent to recover additional reaction product. Acid (e.g., p-TsOH) andwater are then added. The volume ratio of organic solvent to water maybe 25:1, 15:1, 10:1, 5:1, 2:1 or 1:1, and ranges constructed therefrom,such as from about 15:1 to about 5:1. The admixture may be heated withagitation to a reaction temperature, typically at a temperature of from2° C. to about 20° C. below the reflux temperature to the refluxtemperature, and held for a time sufficient to essentially complete theformation of compound formula (IV) such as determined by chromatography(e.g., TLC, GC or HPLC). Upon reaction completion, the reaction mixturemay be quenched, such as with cold water (e.g., less than 10° C. or lessthan 5° C.). The pH of the quenched reaction mixture may then beadjusted with a base to greater than 7, such as about pH 8, about pH 9,about pH 10 or about pH 11. In one embodiment, the base is an aqueousbase such as sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, sodium hydroxide, or ammonium hydroxide.

Upon reaction completion, the step 3 reaction mixture may be separatedinto an aqueous phase and organic phase comprising the compound offormula (IV) in solution. In some optional embodiments, the reactionmixture may be filtered, such as through a filter aid (e.g., celite)prior to phase separation. The aqueous phase may be extracted one ormore times with organic solvent to recover additional compound formula(IV). In one embodiment, the solvent is aprotic. In a particularembodiment, the extracting solvent is suitably isopropyl acetate(“i-PrOAc”).

In some embodiments, the step 3 organic phase(s) may be worked up by,for instance, washing the organic phases with water. The organic phasesmay optionally be dried, such as with a brine solution and/or by theaddition of a solid drying agent such as CaCl₂, MgSO₄ or Na₂SO₄. Soliddesiccants may suitably be removed by filtration, and the collecteddesiccant may optionally be washed with solvent to recover compoundformula (IV) therefrom. In such embodiments, the organic phase(s) may beconcentrated by distillation under partial vacuum or stripping to formcompound formula (IV) residue. The compound formula (IV) residue maythen be dissolved in organic solvent at a temperature below the refluxtemperature. Anti-solvent, such as a non-polar organic solvent asdescribed elsewhere herein, may then be added to the compound formula(IV) solution while cooling, such as to less than about 10° C., toprecipitate/crystallize compound formula (IV) from solution. Compoundformula (IV) solids may be collected by methods known in the art such asfiltration or centrifugation, and optionally washed with anti-solvent.The solids may be dried, such as under partial vacuum, to yield solidcompound formula (IV). The yield to compound formula (IV) from compoundformula (II) for step 3 is at least 80%, at least 85%, at least 90%, atleast 95%, at least 96% or at least 97%. Compound formula (IV) purity isat least 95%, at least 98%, or at least 99%.

One aspect of the disclosure is directed to a process for preparing acompound of formula (VIII) or a salt thereof:

where the process comprises the steps of:

(a) reacting a reaction mixture comprising a compound of formula (IV), acompound of formula (V) or a compound of formula (X), and an organicsolvent to form a compound of formula (VI) according to step 1 below

wherein

B is substituted or unsubstituted indolyl, benzofuranyl,benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl;

each of R^(1a) and R^(1b) is independently hydrogen, fluorine, chlorine,—OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, and—CN, C₃₋₆ cycloalkyl, or C₃— spirocycloalkyl,

n is an integer of 2 or 3,

each of R^(2a) and R^(2b) is independently hydrogen, halogen, —OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, —CN, C₃₋₆cycloalkyl, or C₃₋₆ spirocycloalkyl,

R^(3a) and R^(3b) are independently hydrogen, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, —CN, C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl,phenyl, C₃₋₆ heteroaryl, or C₃₋₆ spirocycloalkyl,

J is phenyl or pyridinyl;

each R⁴ is independently hydrogen, halogen or C₁₋₃ alkyl,

s is an integer from 0 to 2,

LG is a leaving group,

LG and CHO are located in the para position with respect to each otheron J on the compound of formula (V),

PG is an aldehyde protecting group,

LG and CH-PG are located in the para position with respect to each otheron J on the compound formula (X), and

each asterisk independently represents a chiral center wherein thecarbon bearing R^(3a) and R^(3b) is a chiral center when R^(3a) andR^(3b) are different; and

(b) reacting a reaction mixture comprising the compound of formula (VI),an organic solvent, and a compound of formula (VII) or a salt thereof toform a compound of formula (VIII) or a salt thereof according to step 2below

wherein

G is C₁₋₃ alkyl,

p is 0 or 1,

E is substituted or unsubstituted azetidinyl or pyrrolidinyl,

each R⁵ is independently hydrogen, halogen, —OH, —CN, C₁₋₅ alkoxy, orC₁₋₅ hydroxyalkyl,

v is an integer from 1 to 5,

R⁶ is halogen or —CN; and

R¹⁰ is hydrogen or C₁₋₃ alkyl.

B, R^(1a), R^(1b), n, R^(2a), R^(2b), R^(3a), R^(3b) and the asterisk(*) are as defined herein.

In one preferred embodiment, J is phenyl. In another embodiment, J ispyridinyl.

In one embodiment, each R⁴ is independently hydrogen or halogen. In apreferred embodiment, each R⁴ is fluorine. In one embodiment, s is 1 or2. In one embodiment, s is 2. In one preferred embodiment, each R⁴ isfluorine and s is 2.

In one embodiment, G is methylene or ethylene.

In one embodiment, p is 0.

In one embodiment, each R⁵ is independently hydrogen, halogen, —OH, or—CN. In one preferred embodiment, each R⁵ is hydrogen. In oneembodiment, v is 2. In another embodiment, v is 3. In anotherembodiment, v is 5. In a preferred embodiment, each R⁵ is hydrogen and vis 3.

In one preferred embodiment, R⁶ is halogen. In one embodiment, R⁶ is F.In another embodiment, R⁶ is —CN.

In one embodiment, R¹⁰ is hydrogen or methyl. In a preferred embodiment,R¹⁰ is hydrogen

In one embodiment, E is azetidinyl. In another embodiment, E ispyrrolidinyl.

In one embodiment, E has the following structure:

In one embodiment, E is azetidinyl of the following structure:

In one embodiment, E is of the following structure:

where R⁵ is H, v is 2 or 3, and R⁶ is halogen.

In one embodiment, E is azetidinyl of the following structure:

In one embodiment, formula (VIII) is an acid salt. Such acid salt can bea pharmaceutically acceptable salt. In some such embodiments, formula(VIII) is a salt of a pharmaceutically acceptable acid. In someparticular embodiments, formula (VIII) is a salt of a pharmaceuticallyacceptable organic acid. In a preferred embodiment, formula (VIII) is apharmaceutically acceptable salt of tartaric acid. In one embodiment,the compound of formula (VIII) is Compound A as described herein. Inanother embodiment, the compound of formula (VIII) is Compound A(tartrate salt) of Compound A described herein. In another embodiment,formula (VIII) is a pharmaceutically acceptable salt of fumaric acid. Instill another embodiment, the compound of formula (VIII) is Compound B(fumarate salt) of Compound A as described herein.

In one embodiment, formula (VIII) is of any one of the followingstructures, or a pharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof and includingstereoisomers thereof.

In one embodiment, formula (VIII) is of the following structure, or apharmaceutically acceptable salt thereof:

In one embodiment, formula (VIII) is of the following structure:

In one embodiment, formula (VIII) is of the following structure:

Step 1 of the process to synthesize compounds of formula (VIII)comprises reacting a reaction mixture comprising a compound of formula(IV), a compound of formula (V) or a compound of formula (X), and anorganic solvent to form a compound of formula (VI) as set forth herein.In one embodiment, LG is bromine. In a preferred embodiment, whenreacting with compounds of formula (IV) and formula (V), LG and CHO arelocated on J in the para position with respect to each other. In apreferred embodiment, when reacting compounds of formula (IV) andformula (X), LG and CH-PG are located in the para position with respectto each other on J.

The compound of formula (IV) is as described herein.

In one embodiment, the compound of formula (V) is of any one of thefollowing compounds, or a salt thereof:

or a salt thereof.

In some embodiments, formula (X) corresponds to any of the above formula(V) structure, or a salt thereof, but where the aldehyde (—CHO) is aprotected moiety of the structure —CH-PG where PG is an aldehydeprotecting group as defined elsewhere herein.

In some embodiments, formula (VI) is of any one of the followingstructures:

or a salt thereof, including stereoisomers thereof.

In step 2 of the synthesis of compounds of formula (VIII) set forthherein, the compound of formula (VII) can be any one of the followingstructures:

or a salt thereof.

In one embodiment, the salt is an ethane-disulfonate (e.g. a salt ofethane-1,2-disulfonate).

In one embodiment, the compound of formula (VII) has structure

Compound (7) can be prepared according to the examples provided herein,such as, for example, Example 4 or Example 4a.

In one embodiment, Compound 7 is prepared according to the scheme below:

In step 1, a reaction mixture comprising a compound of formula (IV), acompound of formula (V) or a compound of formula (X), and an organicsolvent are reacted to form a compound of formula (VI). In oneembodiment, the organic solvent is a polar protic solvent, a non-polarsolvent, a polar aprotic solvent, or a combination thereof, as describedelsewhere herein. In some non-limiting embodiments, the solvent istoluene. In one embodiment, the solvent is acetonitrile, methyl ethylketone, or methyltetrahydrofuran. In one embodiment, the step 1 reactionmixture further comprises an acid catalyst as described elsewhereherein. In some such non-limiting embodiments, the acid catalyst isacetic acid. The mole ratio of compound (IV) to compound (V) or compound(X) is from about 0.95:1 to about 1.05:1, stoichiometric amounts, or, insome embodiments, compound (V) or compound (X) is in slight molarexcess. The acid catalyst is generally present in stoichiometric excess,such as in an equivalent ratio to compound formula (IV) of about 1.1:1,about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about1.7:1, about 1.8:1, about 2:1, or greater, and ranges constructedtherefrom, such as from about 1.2:1 to about 1.8:1.

In some step 1 embodiments, the reaction mixture may be heated withagitation to a reaction temperature, of from 2° C. to about 30° C. belowthe reflux temperature to the reflux temperature, and held for a timesufficient to essentially complete the reaction to compound formula (VI)such as determined by chromatography (e.g., TLC, GC or HPLC). In thecase of toluene solvent, the reaction temperature is suitably about 65°C., about 70° C., about 75° C., or about 80° C. The reaction productmixture may then be cooled and optionally diluted with additionalsolvent. The reaction product mixture may then be quenched with a base,such as an aqueous solution of a base as described elsewhere herein. Astep 1 reaction product mixture organic phase comprising the compound offormula (VI) may then be isolated and, in some embodiments, worked up bymethods known in the art such as washing with water and/or a brinesolution as described elsewhere herein followed by product isolation asa solid. In one embodiment, the reaction product mixture may be treatedwith activated charcoal, followed by filtration and optional washing ofthe activated charcoal filter cake with solvent. As described elsewhereherein: (i) the organic phase(s) containing compound formula (VI) may beconcentrated by distillation or stripping to reduce the volume, such asby at least 25%, 50%, 100% or more; and (ii) compound formula (IV) maythen be precipitated/crystallized from solution by addition of ananti-solvent followed by optional further concentration.

In some other step 1 embodiments, the step 1 reaction mixture is heatedat reflux for a time to essentially complete the reaction such asdetermined by chromatography (e.g., TLC, GC or HPLC). The reactionmixture may then be cooled and pH-adjusted with a base, such as anaqueous solution of a base, to a pH at which compound formula (VI)precipitates from solution.

In any of the various step 1 embodiments, compound formula (VI) solidsmay be collected by methods known in the art such as filtration orcentrifugation. The solids may be dried, such as under partial vacuum,to yield solid compound formula (VI). The yield to compound formula (VI)from compound formula (V) for steps 1 and 2 is at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least95%.

In step 2, a reaction mixture comprising a compound of formula (VI), acompound of formula (VII) and an organic solvent are reacted to form acompound of formula (VIII). In some embodiments, the organic solvent isa polar aprotic solvent as described elsewhere herein. In somenon-limiting embodiments, the solvent is ACN. The step 2 reactionmixture may further comprise a base, such as an organic base.Non-limiting examples of organic bases include DBU, NMM, DIPEA, and TEA.In some such embodiments, the base is DBU. The step 2 reaction mixturemay further comprise a catalyst, such as a transition metal catalyst. Insome embodiments the catalyst is a Pd catalyst. The mole ratio ofcompound (VII) to compound (VI) is about 0.95:1, about 1:1, about1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1 or about1.5:1, and ranges constructed therefrom, such as from about 1:1 to about1.4:1. The base is generally present in stoichiometric excess, such asin an equivalent ratio to compound formula (VI) of about 1.1:1, about2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, or about8:1, and ranges constructed therefrom, such as from about 3:1 to about7:1. The reaction mixture may be heated with agitation to a reactiontemperature, typically a temperature of from 2° C. to about 30° C. belowthe reflux temperature up to the reflux temperature, and held for a timesufficient to essentially complete the reaction such as determined bychromatography (e.g., TLC, GC or HPLC). In the case of ACN solvent, thereaction temperature is suitably about 65° C., about 70° C., about 75°C., or about 80° C.

After completion the reaction product mixture may suitably be cooled andoptionally diluted with an organic solvent. In one embodiment, thereaction product mixture is diluted with a non-polar solvent asdescribed elsewhere herein. One non-limiting example of a suitablenon-polar solvent is MTBE. The step 2 reaction product mixture may beworked up by methods known to those skilled in the art including waterwash and brine wash. In some such non-limiting embodiments, the work-upmay include washing with an aqueous solution of ammonium chloride, brineand water. In some embodiments, the step 2 reaction product mixture maybe contacted with a metal scavenger known in the art, such as forinstance and without limitation, SiliaMetS Thiol. The reaction productmixture may then be filtered to remove solids prior to isolation ofcompound formula (VIII) therefrom.

In some embodiments, the step 2 reaction product mixture may beconcentrated, such as by vacuum distillation or stripping, and dilutedwith an organic solvent, such as an alcohol (e.g., ethanol), such as ina solvent exchange step. An acid may then be added to the dilutedsolution of compound formula (VIII) followed by cooling to crystallizecompound formula (VIII) as an acid salt. In some particular embodiments,the acid is tartaric acid and compound formula (VIII) is the tartaricsalt. In some such embodiments, the acid is (2R-3R)-tartaric acid(L-(+)-tartaric acid). In another aspect, the acid is (2S-3S)-tartaricacid (D-(−)-tartaric acid). In some such embodiments, the solventcomprises an organic solvent. The crystalline material may be collectedby centrifugation or filtration, optionally washed with solvent, andoptionally dried.

In some other embodiments, compound formula (VIII) may be isolated fromthe step 2 reaction product mixture using methods described elsewhereherein including: (i) distillation, concentration, precipitation (suchas by addition of an anti-solvent or pH adjustment) and/orcrystallization; (ii) solids collection by centrifugation or filtration;(iii) optional washing of the collected solids; (iv) and drying.

The step 2 yield of compound formula (VIII) either as a free base oracid salt is at least 80%, at least 85%, or at least 90%.

Another aspect of the disclosure is directed to a process for preparinga compound of formula (VIII) or a salt thereof, wherein compound formula(VIII) is as described elsewhere herein. The process for preparingformula (VIII) according to this embodiment comprises reaction step 1 asdepicted below:

Each of B, R^(1a), R^(1b), n, R^(2a), R^(2b), R^(3a), R^(3b), R⁴, s, J,R⁵, v, R⁶, R¹⁰, G, p, E, PG and the asterisk are as described elsewhereherein. The CHO moiety and the nitrogen atom linking J and G are locatedin the para position with respect to each other on J. The CH-PG moietyand the nitrogen atom linking J and G are located in the para positionwith respect to each other on J.

In one embodiment, the compound of formula (IX) is:

or a salt thereof.

In one preferred embodiment, the compound of formula (IX) is compound(8a). In some embodiments, formula (XI) corresponds to any of the aboveformula (IX) structures, or a salt thereof, but where the aldehyde(—CHO) is a protected moiety of the structure —CH-PG where PG is analdehyde protecting group as defined elsewhere herein.

In step 1, a reaction mixture comprising a compound of formula (IX) orof formula (XI), a compound of formula (IV) and an organic solvent isreacted to form a compound of formula (VIII), or a salt thereof. In oneembodiment, the organic solvent is a polar solvent, or is a polar proticsolvent. The step 1 reaction mixture further comprises an acid catalystas described elsewhere herein. In a particular embodiment, the acidcatalyst is tartaric acid or fumaric acid. In one embodiment, the acidcatalyst is tartaric acid. In another embodiment, the acid catalyst isfumaric acid. Non-limiting examples of suitable solvents includen-butanol, isopropyl alcohol, n-propanol, i-propanol, ethanol, methanol,and combinations thereof. In some particular embodiments, the solvent isethanol. In one embodiment, the concentration of formula (IX) in thesolvent may suitably be about 25 g/L, about 50 g/L, about 100 g/L %,about 150 g/L, about 200 g/L, about 250 g/L, and up to a concentrationapproaching saturation at the reaction temperature, and rangesconstructed from those concentrations, such as from about 100 g/L toabout 250 g/L. The mole ratio of formula (IX) or of formula (XI) toformula (IV) is suitably about 0.25:1, about 0.3:1, about 0.4:1, about0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 0.95:1,about 1:1, about 1.05:1, about 1.1:1 or about 1.2:1, and rangesconstructed from those ratios, such as from about 0.95:1 to about1.05:1. In one embodiment, formula (IX) or formula (XI) and formula (IV)are present in approximately stoichiometric amounts. In one embodiment,the reaction temperature is below the reaction mixture refluxtemperature. In some other embodiments, the reaction is run at reflux.For instance, where the solvent is ethanol, the reaction temperature maysuitably be from about 50° C. to about 75° C. The reaction time is notnarrowly limited and the reaction is typically continued until theconversion of formula (IX) or formula (XI) to formula (VIII) isessentially complete such as determined by chromatography (e.g., TLC, GCor HPLC).

In one embodiment, formula (VIII) may be formed as a salt of an acid.Suitable acids include inorganic acids and inorganic acids as describedelsewhere herein. In one embodiment, the acid is an organic acid. In apreferred embodiment, the acid is tartaric acid. In another embodiment,the acid is fumaric acid. In one embodiment, formula (VIII) free basemay be dissolved in a suitable solvent, such as a polar protic solvent(e.g., an alcohol such as methanol or ethanol) at an elevatedtemperature followed by addition of an acid. In general, the acid is instoichiometric excess as compared to compound formula (VIII). In somesuch embodiments, the solution temperature and/or concentration offormula (VIII) is adjusted to keep the concentration below saturationand thereby avoid formula (VIII) precipitation and/or crystallization.Following acid addition, the solution may optionally be seeded with acrystalline formula (VIII) salt of the acid. In any of the variousembodiments, the solution is cooled with stirring to form crystallineformula (VIII) salt. The salt may then be collected by methods known inthe art, such as by filtration or centrifugation. In one embodiment, thesalt is collected by filtration. The collected formula (VIII) salt maybe optionally washed, such as with the dissolution solvent, and thendried, such as under partial vacuum.

In a particular embodiment, the step 1 reaction mixture as set forthabove forth synthesis of a compound of formula (VIII) comprises tartaricacid as the acid catalyst, crystalline formula (VIII) tartaric acid, andan alcoholic solvent (e.g. ethanol); the step 1 reaction product mixtureis diluted with the alcoholic solvent; and the resultant slurry iscooled with stirring to form crystalline formula (VIII) tartaric acid.In another embodiment, the step 1 reaction mixture comprises fumaricacid as the acid catalyst, crystalline formula (VIII) fumaric acid, anda solvent. The step 1 yield of compound formula (VIII) as a tartaricacid salt is at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, or at least 95%. In such embodiments, the step 1 reactionscheme is as follows:

Still another aspect of the disclosure is directed to a process forpreparing a compound of formula (IX) or a salt thereof. The process forpreparing compound formula (IX) comprises two reaction steps as depictedbelow:

R⁴, s, LG, PG, R⁵, v, R⁶, R¹⁰, G, p, J, and E are as described elsewhereherein.

Aldehyde protecting groups are defined herein and non-limiting examplesinclude 1,3-dithiane, 1,3-dithiolane, diethyl acetal, dimethyl acetal,ethylene glycol acetal, neopentyl glycol acetal, trimethylsilylcyanohydrin, and triethyl orthoformate.

In step 1, a reaction mixture comprising a compound of formula (X), acompound of formula (VII) or a salt thereof, an organic solvent and acatalyst is reacted to form a compound of formula (XI). In oneembodiment, the solvent is a non-polar solvent as described elsewhereherein. Non-limiting examples of suitable solvents include pentane,hexane, heptane, cyclopentane, MTBE, diethyl ether, toluene, 2-methyltetrahydrofuran (2-MeTHF), benzene, 1,4-dioxane, carbon tetrachloride,chloroform, dichloromethane, and combinations thereof. In some examples,the solvent is toluene. In one embodiment, the catalyst is a transitionmetal catalyst as described herein. In one embodiment, non-limitingexamples of transition metal catalysts include palladium, platinum,gold, ruthenium, rhodium, and iridium catalysts. Non-limiting examplesof suitable catalysts include JohnPhos, XPhos AuC1, XPhos AuNTf2, XPhosPalladacycle, SPhos Palladacycle, tBuXPhos Pd G1, Xphos Pd G2, SPhos PdG2, RuPhos Pd G2, CPhos-Pd-G2, CPhos-Pd-G3, tBuXPhos-Pd-G3,RuPhos-Pd-G3, XPhos-Pd-G3, BrettPhos-Pd-G3, JackiePhos-Pd-G3, tert-butylBrettPhos-Pd-G3, [tert-butyl BrettPhos-Pd (allyl)]OTf), and combinationsthereof. In some embodiments the catalyst is BrettPhos-Pd-G3. In someembodiments, the step 1 reaction mixture further comprises an organicbase as describe elsewhere herein. In some such embodiments, the base isa tert-butoxide such as sodium or potassium tert-butoxide. The moleratio of the compound of formula (VII) to the compound of formula (X) issuitably about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.5:1or about 2:1, and ranges constructed from those ratios, such as fromabout 1.1:1 to about 1.5:1.

In some step 1 embodiments, the reaction mixture may be heated withagitation to a reaction temperature, of from 2° C. to about 30° C. belowthe reflux temperature to the reflux temperature, and held for a timesufficient to essentially complete the reaction to compound formula (XI)such as determined by chromatography (e.g., TLC, GC or HPLC). In thecase of toluene solvent, the reaction temperature is suitably about 50°C., about 55° C., about 60° C., about 65° C., about 70° C., about 75°C., or about 80° C. The reaction time is not narrowly limited and thereaction is typically continued until the conversion of formulae (VII)and (X) to formula (XI) is essentially complete such as determined bychromatography (e.g., TLC, GC or HPLC). After the reaction is completethe reaction product mixture may be suitably quenched. In someembodiments, the step 1 reaction may be quenched with water. Where thereaction is quenched with water, the organic phase comprising thecompound of formula (XI) in solution may be isolated and optionallywashed at least once with water. In some embodiments, the step 1reaction product mixture may be contacted with a metal scavenger knownin the art, such as for instance and without limitation, SiliaMetSThiol. The reaction product mixture may then be filtered to removesolids.

In step 2, the compound of formula (XI) is deprotected to form compoundformula (IX) by combining a solution of compound (XI) in an organicsolvent (e.g., toluene) with an acid and water. The acid is generallypresent in equivalent excess, such an equivalent ratio of acid tocompound (XI) of 1.01:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, or grater. In oneembodiment, the deprotection temperature is not narrowly critical andmay suitably be room temperature. After deprotection, the organic phaseand the aqueous phase (comprising the compound of formula (IX)) areseparated. The organic phase may optionally be washed with water. Theaqueous phase(s) may be treated with a base, such as an inorganic base(e.g., NaOH or KOH), combined with compound formula (IX) seed crystals.The base may suitably be added in equivalent excess. A slurry ofcrystalline compound formula (IX) forms with optional cooling. Compoundformula (IX) solids may be collected by methods known in the art such asfiltration or centrifugation. The solids may be dried, such as underpartial vacuum, to yield solid compound formula (IX). The yield tocompound formula (IX) from compound formula (XI) for steps 1 and 2 is atleast 65%, at least 70%, at least 75%, at least 80% or, at least 85%.

One aspect of the disclosure is directed to a process for preparing acompound of formula (III) or a salt thereof. The process for preparingcompound formula (III) comprises two reaction steps as depicted below:

(1) reacting a reaction mixture comprising a compound of formula (XII),a compound B and an organic solvent to form the compound of formula(XIII) according to step 1 below

where PG is an amine protecting group; and

(2) deprotecting the compound of formula (XIII) to form the compound offormula (III) according to step 2 below

where R^(2a), R^(2b), R^(3a), R^(3b), B, and the asterisk are asdescribed elsewhere herein.

Non-limiting examples of amine protecting groups include ACD, Ac, Bn,CBz, trifluoroacetamide, Boc, MeOZ, FMOC, Bz, PMB, DMPM, PMP, Ts andTroc. In one embodiment, PG is Boc.

In one embodiment, the compound of formula (III) is of the structure

or a salt thereof as described herein.

In some other embodiments, the compound of formula (III) is of thestructure

or a salt thereof as described elsewhere herein.

In step 1, a reaction mixture comprising a compound of formula (XII), Band an organic solvent is reacted to form a compound of formula (XIII).In one embodiment, the organic solvent is a non-polar solvent or a polarsolvent. In one embodiment, the solvent is non-polar. Non-limitingexamples of suitable solvents include pentane, cyclopentane, hexane,cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether,DCM, and combinations thereof. In one embodiment, the solvent is DCM. Insome embodiments, the concentration of B in the solvent may suitably beabout 10 g/L, about 25 g/L, about 50 g/L, about 75 g/L, about 100 g/L %,about 125 g/L, about 150 g/L, about 175 g/L, or about 200 g/L, and up toa concentration approaching saturation at the reaction temperature, andranges constructed from those concentrations, such as from about 25 g/Lto about 125 g/L. The equivalent ratio of B to compound formula (XII) isabout 0.75:1, about 0.9:1, about 1:1, about 1.25:1, about 1.5:1, about1.75:1 or about 2:1, and ranges thereof, such as from about 1.25:1 toabout 1.75:1. The step 1 reaction mixture may further comprise asuitable alkylating agent. Non-limiting examples of alkylating reagentsinclude alkyl lithium (e.g., methyl lithium) such as and organomagnesiumhalide compounds, such as methyl magnesium chloride (e.g., in THF). Theequivalent ratio of B to the alkylating reagent is suitably about0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about 0.95:1, about 1:1,about 1.05:1, about 1.1:1, about 1.15:2, about 1.2:1, about 1.3:1, about1.4:1, about 1.5:1 or greater, and ranges constructed therefrom, such asfrom about 1.1 to about 1.3:1. In one embodiment, the reaction mixturefurther comprises an alkylation catalyst. In some such embodiments, thecatalyst is a transition metal catalyst. In some such embodiments thetransition metal is copper. In a particular embodiment, the catalyst issuitably a transition metal halide, such as copper (I) halide (e.g.,CuCl). In one embodiment, the reaction temperature is about 25° C.,about 20° C., about 15° C., about 10° C., about 5° C., about 0° C.,about −5° C., about −10° C., about −15° C., about −20° C., about −25°C., about −30° C., about −35° C., about −40° C., about −45° C., or about−50° C., and ranges constructed therefrom, such as from about −20° C. toabout 0° C. In one embodiment, the reaction time is not narrowly limitedand the reaction is typically continued until the conversion of B andcompound formula (XII) to compound formula (XIII) is essentiallycomplete such as determined by chromatography (e.g., TLC, GC or HPLC).

After reaction completion, the reaction may be quenched, such as forinstance by the addition of aqueous acid. In one embodiment, the acidmay an organic acid as described elsewhere herein, one non-limitingexample of which is citric acid. The organic phase comprising thecompound of formula (XIII) may then be worked up to dry the compound. Insome such embodiments, the quenched reaction product mixture may beseparated into an aqueous phase and an organic phase comprising thecompound of formula (XIII). The aqueous phase may be washed one or moretimes with an organic solvent, such as the solvent used to form thereaction mixture (e.g., two washes, each with one volume of the solventas compared to the reaction mixture volume). The organic phases may becombined and washed one or more times with brine (e.g., two brinewashes, each with one volume of brine as compared to the reactionmixture volume). The washed organic phases may then be combined withstirring with activated carbon and with a solid drying agent (e.g.,Na₂SO₄). Any activated carbon and solid drying agent may be removed byfiltration or centrifugation. Any collected solids may then beoptionally washed with additional solvent to recover compound formula(XIII) therefrom.

In one embodiment, the solution of compound formula (XIII) may be usedas the starting material for step 2. In one embodiment, solid compoundformula (XIII) may be prepared. In such embodiments, the collectedsolution of compound formula (XIII) in organic solvent may beconcentrated under partial vacuum to form crude compound formula (XIII).Alternatively, solid compound formula (XIII) may beprecipitated/crystallized from solution by the addition of ananti-solvent, such as a non-polar solvent (e.g., 2 volumes of heptane ascompared to the solvent volume in the reaction mixture). The solids maybe collected by filtration or centrifugation and the collected solidsmay be washed with anti-solvent. The solids may be dried under partialvacuum, at a temperature of less than 40° C. to provide finishedcompound formula (XIII). The compound formula (XIII) yield based oncompound (XII) is at typically least 50%, at least 55%, at least 60%, orat least 65%. The purity by HPLC (area percent) is at least 90%, atleast 95%, at least 98% or at least 99%.

In some step 1 embodiments, compound B, a metal catalyst and analkylating agent are combined in a first volume of the solvent at thereaction temperature indicated above. The volume of solvent is suitablyfrom about 30% to about 80% of the total volume of solvent used forstep 1. Thereafter, a solution of compound formula (XII) in theremainder of the solvent is added at the reaction temperature over atime period to form the reaction mixture. The reaction mixture is thenheld a temperature for a time to essentially complete the formation ofcompound formula (XIII), followed by quenching and work-up to a solutionof compound formula (XIII) or dried compound formula (XIII).

In step 2, compound formula (XIII) is deprotected to form compoundformula (III). In any of the various embodiments, a solution of compoundformula (XIII) is suitably deprotected by the addition of an acid. Inone embodiment, solid compound formula (XIII) is dissolved in a polarprotic solvent as described elsewhere herein (such as methanol, ethanolor i-propanol). The concentration of compound formula (XIII) in thesolvent is about 25 g/L, about 50 g/L, about 75 g/L, about 100 g/L,about 125 g/L, about 150 g/L, about 175 g/L, or about 200 g/L, andranges constructed therefrom, such as from about 50 g/L to about 150g/L. Acid addition temperature is not narrowly critical.

In some step 2 embodiments, the acid is an inorganic acid as describedelsewhere herein. A non-limiting example of a suitable inorganic acid isHCl. In one embodiment, the equivalent ratio of acid to compound formula(XIII) is about 1.5:1, about 2.5:1, about 5:1, about 7.5:1, about 10:1,about 12.5:1 or about 15:1 and ranges constructed therefrom, such asfrom about 5:1 to about 15:1. After acid addition, the solution is heldat temperature with stirring until the deprotection of compound formula(XIII) to form compound formula (III) is essentially complete. In oneembodiment, a solvent exchange from the polar protic solvent to anon-polar solvent (as described elsewhere herein) or a polar aproticsolvent (as described elsewhere herein) may be done. In some suchembodiments, the solution of compound formula (III) may be concentratedunder partial vacuum and extracted with the non-polar or polar aproticsolvent. In some such embodiments, the extraction solvent is DCM. Afterextraction, the pH of the aqueous phase may be adjusted to stronglybasic (i.e., greater than pH 11) with a suitable base, such as aqueoussodium hydroxide. After basification, the aqueous phase may then befurther extracted at least once with the extraction solvent. The organicphase(s) may then be dried, such as with brine and/or over a soliddesiccant followed by filtration to remove any solids. Collected solidsmay be optionally washed to recover additional compound formula (III).Solid compound may be isolated from the solution in organic solvent bymethods known in the art. For instance, the solution may be concentratedunder partial vacuum to dryness. Alternatively, the solution may beconcentrated followed by the addition of an anti-solvent to form solidcompound (III) that may be collected by filtration or centrifugation,washed, and dried. The compound formula (III) yield based on compound(XIII) is at typically least 85%, at least 90%, at least 95%, or atleast 97%. The purity by HPLC (area percent) is at least 90%, at least95%, or at least 96%.

In some other step 2 embodiments, the acid is an organic acid asdescribed elsewhere herein. Non-limiting examples of suitable organicacids include sulfonic acids and camphorsulfonic acid (CSA) (e.g.,L-(−)-CSA). In the case of CSA, the equivalent ratio of CSA to compoundformula (XIII) is about 1.5:1, about 2:1 about 2.5:1, about 5:1, about7.5:1, or about 10:1, and ranges constructed therefrom, such as fromabout 2:1 to about 4:1. After acid addition, the solution may be heatedand held at elevated temperature (e.g., about 35° C. to about 60° C.)with stirring to complete deprotection and form the acid salt ofcompound formula (XIII). The acid salt solution/suspension may then becooled, such as to less than about 5° C., to form a suspension of theacid salt of compound formula (XIII). The salt may be collected byfiltration or centrifugation and optionally washed wish solvent. Thesalt may then be dried under partial vacuum to yield the solid salt ofcompound of compound formula (XIII), such as the L-(−)-CSA salt thereof.The compound formula (III) salt yield based on compound formula (XIII)is at typically least 85%, at least 90%, at least 92% or at least 95%.The purity by HPLC (area percent) is at least 90%, at least 95%, atleast 96%, or at least 97%. The compound formula (XIII) salt may bedissolved in water and pH-adjusted to greater than 13, such as about 14,with a strong base thereby forming a suspension comprising solidcompound formula (III) free base. The solid material may be collected byfiltration or centrifugation and optionally washed with chilled water.The solids may then be dried under partial vacuum to yield driedcompound formula (III) free base. The compound formula (III) yield basedon compound (XIII) is at typically at least 80%, at least 85%, or atleast 90%. The purity by HPLC (area percent) is at least 90%, at least95%, at least 96%, or at least 97%.

In one embodiment, a compound of formula (VIII) as prepared herein isfurther recrystallized. In one embodiment the recrystallizationcomprises recrystallizing the compound of formula (VIII) in a 2-stepprocess. The process comprises heating a slurry comprising a compound offormula (VIII) in a mixture of methanol/ethanol, distilling withmethanol, and cooling the mixture. In one embodiment, the mixture ofmethanol/ethanol is a 95:5, 90:10, 85:15, or 80:20 mixture ofmethanol/ethanol. In another embodiment, the mixture of ethanol/methanolis a 90:10 mixture of methanol/ethanol. The mixture can be headed at atemperature of >about 50° C., for example, about 55° C., 60° C., or 65°C. The cooling can be down to about room temperature. In one embodiment,the cooling is to about 20° C., 25° C., or 30° C. The solution can befiltered and dried.

In another embodiment, the recrystallization comprises recrystallizingthe compound of formula (VIII) from MTBE. A base, such as NaOH or KOH isadded to the slurry comprising the compound of formula (VIII) in MTBE.The mixture is stirred at, for example, 15° C., 20° C., 25° C. or 30°C., optionally filtered and distilled with ethanol.

In some embodiments of the process for preparing a compound of formula(III) or a salt thereof, the process further comprises preparing thecompound of formula (XII) or a salt thereof.

The process for preparing the compound of formula (XII) comprisesreaction steps 3a and 3b depicted below:

(1) reacting a reaction mixture comprising a compound of formula (XIV),thionyl chloride, and an organic solvent to form a compound of formula(XV) according to step 3a below

and

(2) reacting a reaction mixture comprising the compound of formula (XV),a catalyst, an oxidizing agent, and an organic solvent to form thecompound of formula (XII) according to step 3b below

R^(2a), R^(2b), R^(3a), R^(3b), and the nitrogen protecting group PG areas described herein.

In step 3a, a reaction mixture comprising a compound of formula (XIV),thionyl chloride, and an organic solvent is reacted to form a compoundof formula (XV). In one embodiment, the organic solvent is a non-polarsolvent or a polar solvent as described elsewhere herein. In oneembodiment, the solvent is non-polar as described elsewhere herein.Non-limiting examples of suitable solvents include pentane,cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane,chloroform, diethyl ether, DCM, and combinations thereof. In someparticular embodiments, the solvent is DCM. In one embodiment, theconcentration of the compound of formula (XIV) in the solvent maysuitably be about 10 g/L, about 25 g/L, about 50 g/L, about 75 g/L,about 100 g/L %, about 125 g/L, about 150 g/L, about 175 g/L, or about200 g/L, and up to a concentration approaching saturation at thereaction temperature, and ranges constructed from those concentrations,such as from about 25 g/L to about 125 g/L. The equivalent ratio ofthionyl chloride to compound formula (XIV) is about 1:1, about 1.25:1,about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, or about 2.5:1, andranges thereof, such as from about 1.25:1 to about 1.75:1. In oneembodiment, the reaction temperature is about 10° C., about 5° C., about0° C., about −5° C., or about −10° C., and ranges constructed therefrom,such as from about −5° C. to about 5° C. In one embodiment, the reactiontime is not narrowly limited and the reaction is typically continueduntil the conversion of compound formula (XIV) is essentially completesuch as determined by chromatography (e.g., TLC, GC or HPLC). The step3a reaction mixture may further comprise a base, a non-limiting exampleof which is imidazole. In such embodiments, the equivalent ratio ofthiolation reagent to thionyl chloride may be about 1:1, about 2:1,about 3:1 or about 4:1. The step 3a reaction mixture may furthercomprise a base, such as an organic base as described elsewhere herein.In some such embodiments, the base may be TEA. In such embodiments, theequivalent ratio of the base to compound formula (XIV) is about 1.25:1,about 1.5:1, about 1.75:1, about 2:1, about 2.25:1, about 2.5:1, about3:1, about 3.5:1 or about 4:1, and ranges constructed therefrom, such asfrom about 1.5:1 to about 2.5:1.

In some particular step 3a embodiments, a solution of the base (e.g.,imidazole) in the solvent is formed to which the thionyl chloride isadded with stirring while maintaining the reaction temperature. Compoundformula (XIV) in the solvent may then be added with stirring whilemaintaining the reaction temperature, followed by addition of the basewith stirring while maintaining the reaction temperature. The reactionmixture is then maintained at the reaction temperature with stirringuntil the conversion of compound formula (XIV) to form a reactionproduct mixture comprising the compound of formula (XV) is essentiallycomplete.

In any of the various step 3a embodiments, the reaction product mixturemay be worked up by methods known to those skilled in the art. Forinstance, the step 3a reaction mixture may be quenched with chilledwater (e.g., 0.25 to 2 volumes of water per volume of organic solvent inthe step 3a reaction product mixture). An organic phase comprising thecompound of formula (XV) in solution may be isolated and the isolatedaqueous phase may be extracted with organic solvent to recoveradditional compound formula (XV). The organic phases may be combined andwashed with an aqueous acid solution, and aqueous base solution, andbrine. A non-limiting example of an aqueous acid solution is a solutionof a weak acid, such as a citric acid. A non-limiting example of a basesolution is a solution of a weak base, such as sodium bicarbonate.

In step 3b, a reaction mixture comprising formula (XV) in solution inthe organic solvent is combined with a catalyst and an oxidizing agent,and reacted to form a reaction product mixture comprising the compoundof formula (XII). In one embodiment, the catalyst is a redox activemetal catalyst as described elsewhere herein. Non-limiting examples ofsuitable catalysts include NiCl₂, RuCl₃, CoCl₂, FeCl₃, FeCl₂, and MnCl₂.Non-limiting examples of suitable oxidants include NaIO₄, NaOCl, andOxone. In some embodiments the reaction mixture further comprises water.The volume ratio of water to organic solvent is suitably about 0.25:1,about 0.5:1, about 0.75:1, about 1:1, about 1.25:1, about 1.50:1, about1.75:1, about 2:1 or about 2.5:1, and ranges constructed therefrom, suchas from about 0.5:1 to about 1.5:1. The reaction temperature is suitablyfrom about 5° C. to about 50° C. The reaction mixture is maintained atthe reaction temperature with stirring until the conversion of compoundformula (XV) to form a reaction product mixture comprising the compoundof formula (XII) is essentially complete such as determined bychromatography (e.g., TLC, GC or HPLC).

The step 3b reaction product mixture may be worked up by methods knownto those skilled in the art. For instance, the organic phase comprisingthe compound of formula (XII) in solution may be isolated and theaqueous phase may be optionally filtered and then extracted with organicsolvent to recover compound formula (XII). The organic phase(s) mayoptionally be washed with a reducing agent (e.g., sodium thiosulfate)and with brine. The organic phase(s) may be dried with a solid desiccant(e.g., sodium sulfate) followed by filtration to remove solids andoptional washing thereof with organic solvent. Solid compound formula(XII) from solution in organic solvent by methods known in the art. Forinstance, the solution may be concentrated under partial vacuum todryness. Alternatively, the solution may be concentrated followed by theaddition of an anti-solvent to form solid compound (XII) that may becollected by filtration or centrifugation, washed, and dried. Thecompound formula (XII) yield based on compound (XIV) is at typicallyleast 85%, at least 90%, or at least 92%. The purity by HPLC (areapercent) is at least 95%, at least 98%, or at least 99%.

Chiral primary amines can be produced using a stereospecifictransaminase either via an asymmetric transamination of a prochiralketone or kinetic resolution of a racemic amine. The transamination is areaction equilibrium consisting of a pair of amines and ketones (donorsand acceptors) and the reaction conditions applied shift the equilibriumto the chiral target amine. In one such aspect, the amine donor isalanine or 2-propylamine. In one embodiment, the amine acceptor ispyruvate or acetone.

Thus, further provided herein is a process for preparing a compound offormula (XX) or a salt thereof, wherein conversion of the chiraltryptamine comprises using enzymatic transformation:

The process for preparing compound formula (XX) comprises contacting acompound of formula (XXI)

with a protein transaminase to form a compound of formula (3):

The process further comprises the presence of one or more amine donors.In one embodiment the amine donor is alanine or iso-propyl amine.

The contacting described above can be performed in mixed aqueous organicsolvent systems. For example, the transaminase reaction can be performedin aqueous buffer with an organic co-solvent such as cyclo-hexane,methyl-cyclo-hexane, iso-octane, DMSO, acetonitrile, or acetone. Suchco-solvents can be present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, or 50% v/v.

The mixed organic/aqueous solvent system (micro-aqueous reaction system)can, in certain instances, comprise one or more organic solventscomprising a small amount of aqueous buffer. In one embodiment, thecontacting is performed in TBME, dibutyl ether, CPME, toluene, ethylacetate, butyl acetate, iso-propyl acetate, butyl butyrate, ethylbutyrate or iso-butyl acetate comprising less than 15, 14, 13, 12, 11,10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% v/v aqueous buffer. When performed inorganic solvent, the transaminase can be immobilized to a solid support.

In another embodiment, the conversion of compound (XXI) to compound (3)is above at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.In another aspect, the conversion is above 90%. In another embodiment,the conversion is above 95%.

The reductive amination completed by the transaminase can yield thecompound of formula (3) in at least 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or 100% enantiomeric excess (EE). In certain instances, thetransaminase converts the compound of formula (XXI) to (3) at an EEgreater than 99%.

In one embodiment, the asymmetric transamination of the compound offormula (XXI) is performed using the scheme below:

The compound of formula (3) is contacted with a compound of formula (II)as described herein:

to form compound formula (XX).

R^(1a), R^(1b) and n are as described elsewhere herein. In oneembodiment, R^(1a) and R^(1b) are independently fluorine.

In one embodiment, compound formula (XX) is of the structure:

The protein transaminase can be selected from Table 6. In one suchaspect, the transaminase is (R)-selective. In one embodiment, thetransaminase is TA-P2-A01. In one embodiment, the protein transaminaseis selected from a (S)-enantioselective transaminase of SEQ ID NO: 1,SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4.

Further provided herein are methods of enzymatically synthesizing acompound of formula (3) through kinetic resolution of a racemic amine inthe presence of an amine acceptor and a transaminase. The reaction canbe performed in conditions as described herein, for example, in mixedaqueous/organic solvent systems as described herein. In one such aspect,the reaction is performed in aqueous buffer comprising acetonitrile.Such kinetic resolution can yield the compound of formula (3) in an EEof at least 99%, requiring above 50% conversion rate. Kinetic resolutioncomprises use of an (S)-selective transaminase as described herein forperforming the kinetic resolution. In one embodiment, the transaminaseis selected from Table 6.

One embodiment of the disclosure is directed to a compound of formula(XVI):

R⁴, S, R¹⁰, G, and p are as defined herein.

each of R^(7a), R^(7b), R^(8a) and R^(8b) is independently hydrogen,halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ hydroxyalkyl, or —CN. In oneembodiment, each of R^(7a), R^(7b), R^(8a) and R^(8b) is independentlyhydrogen, fluorine, —CH₃, or —CN. In one embodiment, each of R^(7a),R^(7b), R^(8a) and R^(8b) is hydrogen.

y is an integer of 1 or 2, x is an integer of 1 or 2, and the total of xand y is 2 or 3.

M is C_(1-s) alkyl;

r is 0 or 1; and

R⁹ is halogen or —CN.

In one embodiment, M is —CH₂CH₂CH₂—, p is 1, and R⁹ is fluorine.

In one embodiment, M is —CH₂CH₂CH₂—, p is 1, and R⁹ is —CN.

In one embodiment, the compound of formula (XVI) is:

or a salt thereof.

In a particular embodiment, the compound of formula (XVI) is:

In another aspect provided herein is a compound having the structure:

In another aspect provided herein is a process to make a compound havingformula:

wherein the process is performed as set forth in Scheme A below and inaccordance with the embodiments and embodiments provided herein.

BrettPhos Pd G3[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

In still another embodiment, of the disclosure is a process to make acompound having formula:

wherein the process is performed as set forth in Scheme B below and inaccordance with the embodiments and embodiments provided herein.

The processes for synthesis of Compound B above (e.g. Scheme A and B)can further comprise recrystallization according to Scheme C or D below:

In one embodiment, compounds (3) and (4) as described herein andprovided in Scheme A and Scheme B, and optionally Scheme C or D, aboveare synthesized according to Scheme E below and in accordance with theembodiments and embodiments provided herein.

Further provided herein is a process for preparing a compound of formula(XXIII) or a salt thereof:

B, R^(1a), R^(1b), n, R^(2a), R^(2b), R^(3a), R^(3b), R⁴, s, G, R⁵, v,R⁶, E, and the asterisks are as defined herein.

In one embodiment, the compound of formula (XXIII) is an acid salt. Insuch embodiments, the compound of formula (VIII) is a salt of an acid.In a preferred embodiment, the compound of formula (XXIII) is a salt oftartaric acid. In some embodiments, the compound of formula (XXIII) is asalt of fumaric acid.

In one embodiment, the compound of formula (XXIII) is of any one of thefollowing structures, or a tartaric acid salt thereof:

In another embodiment, the compounds above are a fumaric acid salt.

In one embodiment, the compound of formula (XXIII) is of the followingstructure, or a pharmaceutically acceptable salt thereof:

The process for preparing the compound of formula (XXIII) comprises tworeaction steps as depicted below:

LG is as defined herein.

The variables of formulae (IV), (V) and (VI) are as described herein.

In one embodiment, the compound of formula (XXIV) is of any one of thefollowing structures, or a salt thereof:

One embodiment of the disclosure is directed to a process for preparinga compound of formula (XXIII) or a salt thereof, wherein the compound offormula (XXIII) is as described herein. The process for preparing thecompound of formula (XXIII) according to this embodiment comprisesreaction step 1 as depicted below:

Each of B, R^(1a), R^(1b), n, R^(2a), R^(2b), R^(3a), R^(3b), R⁴, s, J,R⁵, v, R⁶, G, p, E and the asterisk are as described elsewhere herein.The CHO moiety and the nitrogen atom linking J and G are located in thepara position with respect to each other on J.

In some embodiments, compound formula (XXIV) is:

or a salt thereof

One embodiment of the disclosure is directed to a process for preparinga compound of formula (XXVII) or a salt thereof.

The process for preparing compound formula (XXVII) comprises tworeaction steps as depicted below:

R⁴, s, LG, R⁵, v, R⁶, G, p, E and PG are as described herein.

Further provided herein are solid forms, formulations comprising suchsolid forms, and methods of using such solid forms of Compound A:

and having the name3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol,including a pharmaceutically acceptable salt thereof.

In one embodiment provided herein are solid forms of Compound A.Compound A can be a freebase as described herein existing in anamorphous solid form. In another embodiment, Compound A is a crystallinesolid as described herein. In still another embodiment, Compound A is acrystalline tartrate salt having the structure:

In another aspect provided herein are crystalline solid forms ofCompound A as a fumarate salt having the structure:

In still another aspect provided herein are solid forms of Compound Amalonate salts having the structure:

Solid forms described herein can be crystalline. In another embodiment,the solid form is a single-component solid form. Solid forms describedherein can be solvates, hydrates, anhydrates, or salts as set forthherein. In one embodiment, solid forms described herein comprisetartrate salts. In another embodiment, solid forms described hereincompris anhydrates of Compound B. In another embodiment, solid formsdescribed herein comprise fumarate salts. In still another embodiment,solid forms described herein comprise phosphate salts or other salts.

While not intending to be bound by any particular theory, solid formscan be characterized by physical properties such as, for example,stability, solubility and dissolution rate, density, compressibility,hardness, morphology, cleavage, stickiness, solubility, water uptake,electrical properties, thermal behavior, solid-state reactivity,physical stability, and chemical stability) affecting particularprocesses (e.g., yield, filtration, washing, drying, milling, mixing,tableting, flowability, dissolution, formulation, and lyophilization)which make certain solid forms suitable for the manufacture of a soliddosage form. Such properties can be determined using particularanalytical chemical techniques, including solid-state analyticaltechniques (e.g., X-ray diffraction, microscopy, spectroscopy andthermal analysis), as described herein.

The solid forms described herein, including salt forms, crystallineforms, and amorphous solids can be characterized by a number of methodsincluding, for example, single crystal X-ray diffraction, X-ray powderdiffraction (XRPD), microscopy (e.g., scanning electron microscopy(SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC),dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), andhot-stage microscopy), spectroscopy (e.g., infrared, Raman, andsolid-state nuclear magnetic resonance), ultra-high performance liquidchromatography (UHPLC), proton nuclear magnetic resonance (spectrum.

Techniques for characterizing crystal forms and amorphous solidsinclude, for example, thermal gravimetric analysis (TGA), differentialscanning calorimetry (DSC), X-ray powder diffractometry (XRPD),single-crystal X-ray diffractometry, vibrational spectroscopy, e.g.,infrared (IR) and Raman spectroscopy, solid-state and solution nuclearmagnetic resonance (NMR) spectroscopy (including ¹H NMR and F NMR),scanning electron microscopy (SEM), electron crystallography andquantitative analysis, particle size analysis (PSA), surface areaanalysis, solubility studies, and dissolution studies.

The purity of the solid forms provided herein can be determined bystandard analytical methods, such as thin layer chromatography (TLC),gel electrophoresis, gas chromatography, ultra-high performance liquidchromatography (UHPLC), and mass spectrometry (MS).

Compound B, Form A:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form A. Form A is a crystalline solid form of Compound B.In one embodiment, Form A is an acetone solvate of Compound B. In oneembodiment, Form A is a crystalline acetone solvate tartrate salt ofCompound A.

In another embodiment, Form A of Compound B is obtained by slurrying inacetone followed by evaporation. Form A can prepared according to themethods and examples described herein.

In one embodiment, a solid form provided herein, e.g., Form A, is atartrate salt of Compound A (i.e. Compound B), and is crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD of a solid form provided herein, e.g., Form A,is substantially as shown in FIG. 1. In another embodiment, a solid formprovided herein, e.g., Form A, has one or more characteristic XRPD peaksat approximately 4.64, 8.26, 9.28, 11.18, 11.49, 11.96, 12.54, 13.77,14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84, 19.32, 19.82,20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54, 23.94, 24.81, or25.96±0.1° 2θ, as depicted in, for example, FIG. 1 and as found in Table16 herein. In still another embodiment, a solid form provided herein,e.g., Form A, has at least 3, at least 5, at least 7, or at least 10XPRD peaks at approximately 4.64, 8.26, 9.28, 11.18, 11.49, 11.96,12.54, 13.77, 14.22, 14.61, 15.09, 15.56, 16.01, 17.35, 18.55, 18.84,19.32, 19.82, 20.26, 21.34, 21.63, 21.92, 22.52, 22.97, 23.28, 23.54,23.94, 24.81, or 25.96±0.1° 2θ, as depicted in, for example, FIG. 1 andas found in Table 16 herein. In yet another embodiment, a solid formdescribed herein, e.g., Form A, has one, two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen,sixteen, seventeen, eighteen, nineteen, twenty, or all of thecharacteristic XRPD peaks as set forth in Table 16.

In still another embodiment, a solid form provided herein, e.g., Form A,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 12.54, 14.61, 16.01, 19.32,20.26, 21.63, 23.28, 23.54, 23.94, or 24.81±0.1° 2θ, as depicted in, forexample, FIG. 1 and as found in Table 16 herein. In another embodiment,a solid form provided herein, e.g., Form A, has one, two, three, four,or five characteristic XRPD peaks at approximately 19.32, 20.26, 21.63,23.28, or 24.81±0.1° 2θ, as depicted in, for example, FIG. 1 and asfound in Table 16 herein. In another embodiment, a solid form providedherein, e.g., Form A, has one, two, three, four, or five characteristicXRPD peaks at approximately 19.32, 20.26, 21.63, 23.28, or 24.81±0.05°2θ, as depicted in, for example, FIG. 1 and as found in Table 16 herein.

In one embodiment described herein, is a solid form, e.g., Form A,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 2. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 7.2% of the total mass of the samplebefore approximately 125° C.

In another embodiment described herein, is a solid form, e.g., Form A,having a DSC thermogram substantially as depicted in FIG. 2 comprisingdesolvation event at about 124° C. and a melting temperature of havingan onset temperature of about 164° C. and a peak maximum temperature ofabout 171° C.

In another embodiment described herein, is a solid form, e.g., Form A,having a Polarized Light Microscopy image as depicted in FIG. 3.

In still another embodiment, Form A is pure. In certain embodiments,pure Form A is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, the purity of Form A is no less thanabout 95%, no less than about 96%, no less than about 97%, no less thanabout 98%, no less than about 98.5%, no less than about 99%, no lessthan about 99.5%, or no less than about 99.9%.

Compound B, Form B:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form B. Form B is a crystalline solid form of Compound B.In one embodiment, Form B is an anhydrate of Compound B. In anotherembodiment, Form B is an anhydrate tartrate salt of Compound A.

In one embodiment, Form B of Compound B is obtained by slurryingCompound B in ethyl acetate at RT for about 24 hours. In anotherembodiment, Form B of Compound B is obtained by slurrying Compound B inacetone:water (e.g. 90:10, 95:5, 96:4, 97:3, 99:1 v/v) at about 50° C.for about 6 hours. In still another embodiment, Form B of Compound B isobtained by slurrying Compound B in ethanol.

In certain instances, Form B of Compound B is obtained by slurryingCompound B in a solvent system comprising ≥95% acetone (e.g. ≥95:5acetone:water). Form B of Compound B is then isolated from the slurryby, for example, centrifugation or filtration. In another embodiment,Form B of Compound B is obtained from either Form A or Form F asdescribed herein. In one embodiment, Form A of Compound B is reslurriedin ethanol (e.g. 100% ethanol) for 10, 12, 16, or 24 hours (e.g.overnight) to obtain Form B. In one embodiment, Form F is converted toForm D as described herein in the presence of water. The mixture canthen be slurried in neat ethanol (at for example about 50° C.) or 95:5or 97:3 acetone:water (v/v) to form Form B. Mixtures can optionally beseeded with Form B crystals.

Form B can be prepared according to the methods and examples describedherein. Thus, provided herein is a method of preparing Form B where themethod comprises slurrying Compound B in a solvent system comprisingacetone or aqueous mixtures of acetone water (e.g., 50%, 90%, 95%, 96%,97%, 98% and 99% acetone v/v). In one embodiment, the solvent system forcrystalizing Form B comprises ≥95% acetone. In one embodiment, thesolvent system for Form B comprises 96:4 acetone:water. The mixtures canbe slurried at RT for about 120 hrs. The mixtures can be filtered andanalyzed as described herein (e.g., XRPD). In one embodiment, Form B isprepared according to the methods and/or examples set forth herein.

In one embodiment, a solid form provided herein, e.g., Form B, is atartrate salt of Compound A, and is crystalline, as indicated by X-raypowder diffraction pattern (XRPD) measurements. In one embodiment, theXRPD of a solid form provided herein, e.g., Form B, is substantially asshown in FIG. 4. In another embodiment, a solid form provided herein,e.g., Form B, has one or more characteristic XRPD peaks at approximately7.68, 11.49, 12.54, 14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24,19.16, 19.42, 19.89, 20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67,25.07, 25.91±0.1° 2θ, as depicted in, for example, FIG. 4 and as foundin Table 17 herein. In still another embodiment, a solid form providedherein, e.g., Form B, has at least 3, at least 5, at least 7, or atleast 10 characteristic XPRD peaks at approximately 7.68, 11.49, 12.54,14.24, 15.30, 15.55, 16.01, 16.63, 17.37, 18.24, 19.16, 19.42, 19.89,20.24, 21.81, 22.52, 22.99, 23.25, 23.57, 24.67, 25.07, 25.91±0.1° 2θ,as depicted in, for example, FIG. 4 and as found in Table 17 herein. Inyet another embodiment, a solid form described herein, e.g., Form B, hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, or all of the characteristic XRPDpeaks as set forth in Table 17.

In still another embodiment, a solid form provided herein, e.g., Form B,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 11.49, 12.54, 15.30, 15.55,19.16, 19.42, 20.24, 23.25, 24.67, or 25.91±0.1° 2θ, as depicted in, forexample, FIG. 4. In still another embodiment, a solid form providedherein, e.g., Form B, has one, two, three, four, or five characteristicXRPD peaks at approximately 11.49, 12.54, 19.16, 19.42, or 24.67±0.1°20, as depicted in, for example, FIG. 4. In still another embodiment, asolid form provided herein, e.g., Form B, has one, two, three, four, orfive characteristic XRPD peaks at approximately 11.49, 12.54, 19.16,19.42, or 24.67±0.05° 2θ, as depicted in, for example, FIG. 4.

In one embodiment described herein, is a solid form, e.g., Form B,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 5. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 3.5% of the total mass of the sample.

In another embodiment described herein, is a solid form, e.g., Form B,having a DSC thermogram substantially as depicted in FIG. 5 comprisingan endothermic event with an onset temperature of about 171° C. and apeak maximum temperature of about 179° C.

In another embodiment described herein, is a solid form, e.g., Form B,having a ¹³C and ¹⁹F NMR spectrum substantially as depicted in FIG. 6and FIG. 7, respectively.

In another embodiment described herein, is a solid form, e.g., Form B,having a water sorption-desorption profile as depicted in FIG. 8. Thesolid form, e.g., Form B of Compound B, absorbs about 1.2% w/w moistureup to 90% relative humidity (RH) at about 25° C.

In another embodiment described herein, is a solid form, e.g., Form B,having a Scanning Electron Microscope (SEM) image and PLM image asdepicted in FIG. 9a and FIG. 9b , respectively. The sample comprises ofdense spherical aggregates.

In another embodiment described herein, is a solid form, e.g., Form B,having a particle size distribution (PSD) as depicted in FIG. 9 c.

In still another embodiment, a solid form, e.g., Form B, remainssubstantially unchanged following compression as described herein. FIG.22, FIG. 23, and FIG. 24, respectively show XRPD, ¹⁹F SSNMR, and DSC ofForm B of Compound B and compare the compound before and aftercompression as described herein.

In still another embodiment, Form B is substantially pure. In certainembodiments, the pure Form B is substantially free of other solid forms,e.g., amorphous solid. In certain embodiments, the substantially pureForm B is substantially free of Form A, Form D, or Form F. In certainembodiments, the purity of Form B is no less than about 95%, no lessthan about 96%, no less than about 97%, no less than about 98%, no lessthan about 98.5%, no less than about 99%, no less than about 99.5%, orno less than about 99.9%.

Compound B, Form C:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form C. Form C is a crystalline solid form of Compound B.In one embodiment, Form C is a THF solvate of Compound B.

In one embodiment, Form C of Compound B is obtained by slurryingCompound B in THF. The mixture can then be filtered. Form C can beprepared according to the methods and examples described herein.

In one embodiment, a solid form provided herein, e.g., Form C, istartrate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD is substantially as shown in FIG. 10.

In one embodiment described herein, is a solid form, e.g., Form C,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 11. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 6.8% of the total mass of the sample.

In another embodiment described herein, is a solid form, e.g., Form C,having a DSC thermogram substantially as depicted in FIG. 11 comprisingan endothermic event with an onset temperature of about 118° C. and apeak maximum temperature of about 125° C.

In still another embodiment, Form C is pure. In certain embodiments, thepurity of Form C is no less than about 95%, no less than about 96%, noless than about 97%, no less than about 98%, no less than about 98.5%,no less than about 99%, no less than about 99.5%, or no less than about99.9%.

Compound B, Form D:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form D. Form D is a crystalline solid form of Compound B.In one embodiment, Form D is a hydrate of Compound B. In anotherembodiment, Form D is a monohydrate of Compound B.

In one embodiment, Form D of Compound B is obtained by slurryingCompound B in 100% ethanol for about 48 hours. The mixture can then befiltered.

In one embodiment, a solid form provided herein, e.g., Form D, is atartrate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inanother embodiment, Form D is a hydrate of Compound B. In oneembodiment, the XRPD of a solid form provided herein, e.g., Form D, issubstantially as shown in FIG. 12. In another embodiment, a solid formprovided herein, e.g., Form D, has one or more characteristic XRPD peaksat approximately 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11, 14.66,15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34, 19.10,20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56±0.1° 2θ, asdepicted in, for example, FIG. 12 and as found in Table 19. In stillanother embodiment, a solid form provided herein, e.g., Form D, has atleast 3, at least 5, at least 7, or at least 10 characteristic XRPDpeaks at approximately 7.32, 10.99, 11.31, 12.18, 13.23, 13.48, 14.11,14.66, 15.14, 15.70, 16.03, 16.21, 16.54, 17.24, 17.63, 18.11, 18.34,19.10, 20.20, 20.58, 21.16, 21.47, 21.89, 22.76, 23.33, or 23.56±0.1°2θ, as depicted in, for example, FIG. 12 and as found in Table 19. Inyet another embodiment, a solid form described herein has one, two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, fifteen, or all of the characteristic XRPD peaks asset forth in Table 19.

In still another embodiment, a solid form provided herein, e.g., Form D,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 11.31, 15.70, 16.54, 19.10,20.58, 21.16, 21.47, 21.89, 22.76, or 23.33±0.1° 2θ, as depicted in, forexample, FIG. 12. In still another embodiment, a solid form providedherein, e.g., Form D, has one, two, three, four, or five characteristicXRPD peaks at approximately 11.31, 15.70, 16.54, 19.10, or 22.76±0.1°2θ, as depicted in, for example, FIG. 12. In still another embodiment, asolid form provided herein, e.g., Form D, has one, two, three, four, orfive characteristic XRPD peaks at approximately 11.31, 15.70, 16.54,19.10, or 22.76±0.05° 2θ, as depicted in, for example, FIG. 12.

In one embodiment described herein, is a solid form, e.g., Form D,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 13. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 1.4% of the total mass of the samplebefore approximately 150° C.

In another embodiment described herein, is a solid form, e.g., Form D,having a DSC thermogram substantially as depicted in FIG. 13 comprisingan endothermic event having an onset temperature of about 55° C. and apeak maximum temperature of about 82° C. followed by a secondendothermic event with an onset temperature of about 165° C. and a peakmaximum temperature of about 172° C.

In still another embodiment, Form D is pure. In certain embodiments,Form D is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, Form D is substantially free of Form A,Form B, or Form F. In certain embodiments, the purity of Form D is noless than about 95%, no less than about 96%, no less than about 97%, noless than about 98%, no less than about 98.5%, no less than about 99%,no less than about 99.5%, or no less than about 99.9%.

Compound B, Form E:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form E. Form E is a solid form of Compound B. In oneembodiment, Form E is a DMSO solvate of Compound B.

In one embodiment, Form E of Compound B is obtained by slurryingCompound B in DMSO and adding IPAc, for about 24 hours. The mixture canthen be filtered. Form E can be prepared according to the methods andexamples described herein.

In one embodiment, a solid form provided herein, e.g., Form E, is atartrate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD is substantially as shown in FIG. 14.

In one embodiment described herein, is a solid form, e.g., Form E,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 15. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 8.3% of the total mass of the sample.

In another embodiment described herein, is a solid form, e.g., Form E,having a DSC thermogram substantially as depicted in FIG. 15 comprisinga first endotherm with an onset temperature of about 126° C. and a peakmaximum temperature of about 134° C. and a second endothermic event withan onset temperature of about 143° C. and a peak maximum temperature ofabout 147° C.

In still another embodiment, Form E is pure. In certain embodiments,Form E is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, the purity of Form E is no less thanabout 95%, no less than about 96%, no less than about 97%, no less thanabout 98%, no less than about 98.5%, no less than about 99%, no lessthan about 99.5%, or no less than about 99.9%.

Compound B, Form F:

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form F. Form F is a crystalline solid form of Compound B.In one embodiment, Form F is an anhydrate of Compound B. In anotherembodiment, Form F is an anhydrate tartrate salt of Compound A.

In one embodiment, Form F of Compound B is obtained by slurryingCompound B in 100% ethanol at RT or at 50° C. for about 8, 10, 12, 15,20, or 25 hours (e.g. overnight). In another embodiment, Form F can beobtained by slurrying Compound B in ethanol/water (e.g. 65:35 v/v). Theslurry of Compound B to obtain Form F can optionally include seedingwith Form B described herein. The slurry can be filtered to obtain FormF. Form F can also be obtained by slurrying at RT in 100% DI water, 1:1acetone/water or 100% acetone. Slurries of Form F in neat solvents canbe maintained at RT. In one embodiment, Form F can be obtained from 1:1acetone:water mixture agitated at 5° C. In still another embodiment,Form F can be obtained by slurrying Compound B in 95:5 acetone:water and97:3 acetone:water mixtures at 50° C. for about 2 hours and cooling toRT. Form F can be prepared according to the methods and examplesdescribed herein.

In one embodiment, a solid form provided herein, e.g., Form F, is atartrate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD of a solid form provided herein, e.g., Form F,is substantially as shown in FIG. 16. In another embodiment, a solidform provided herein, e.g., Form F, has one or more characteristic XRPDpeaks at approximately 3.92, 10.54, 11.72, 12.52, 14.22, 15.40, 15.54,15.90, 16.48, 16.84, 17.29, 18.26, 18.47, 19.39, 19.66, 20.00, 20.50,20.65, 21.16, 21.28, 21.95, 22.97, 23.49, 23.70, 23.94, 24.31, 24.67, or24.99±0.1° 2θ, as depicted in, for example, FIG. 16 and as found inTable 20 herein. In still another embodiment, a solid form providedherein, e.g., Form F, has at least 3, at least 5, at least 7, or atleast 10 characteristic XPRD peaks at approximately 3.92, 10.54, 11.72,12.52, 14.22, 15.40, 15.54, 15.90, 16.48, 16.84, 17.29, 18.26, 18.47,19.39, 19.66, 20.00, 20.50, 20.65, 21.16, 21.28, 21.95, 22.97, 23.49,23.70, 23.94, 24.31, 24.67, or 24.99±0.1° 2θ, as depicted in, forexample, FIG. 16 and as found in Table 20 herein. In yet anotherembodiment, a solid form described herein, e.g., Form F, has one, two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, fifteen, twenty, twenty-five, or all of thecharacteristic XRPD peaks as set forth in Table 20.

In still another embodiment, a solid form provided herein, e.g., Form F,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 12.52, 15.90, 19.66, 20.65,or 24.99±0.1° 2θ, as depicted in, for example, FIG. 16. In still anotherembodiment, a solid form provided herein, e.g., Form F, has one, two,three, four, or five characteristic XRPD peaks at approximately 12.52,15.90, 19.66, 20.65, or 24.99±0.1° 2θ, as depicted in, for example, FIG.16. In still another embodiment, a solid form provided herein, e.g.,Form F, has one, two, three, four, or five characteristic XRPD peaks atapproximately 12.52, 15.90, 19.66, 20.65, or 24.99±0.05° 2θ, as depictedin, for example, FIG. 16.

In one embodiment described herein, is a solid form, e.g., Form F,having a DVS isotherm plot corresponding substantially to therepresentative DVS isotherm plot as depicted in FIG. 17.

In another embodiment described herein, is a solid form, e.g., Form F,having a DSC thermogram substantially as depicted in FIG. 18 comprisingan endothermic event with an onset temperature of about 162° C. and apeak maximum temperature of about 167° C.

In still another embodiment, Form F is pure. In certain embodiments,pure Form F is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, the purity of the Form F is no less thanabout 95%, no less than about 96%, no less than about 97%, no less thanabout 98%, no less than about 98.5%, no less than about 99%, no lessthan about 99.5%, or no less than about 99.9%.

Compound B, Form G

In certain embodiments, provided herein is a solid form of Compound Bdesignated as Form G. Form G is a solid form of Compound B. In oneembodiment, Form G is a methanol solvate of Compound B. In anotherembodiment, Form F is a methanol solvate tartrate salt of Compound A.

In one embodiment, Form G of Compound B is obtained by slurryingCompound B in methanol and slowly evaporating the methanol. The mixturecan be filtered. Form G can be prepared according to the methods andexamples described herein.

In one embodiment, a solid form provided herein, e.g., Form G, is atartrate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD of a solid form provided herein, e.g., Form G,is substantially as shown in FIG. 19. In another embodiment, a solidform provided herein, e.g., Form G, has one or more characteristic XRPDpeaks at approximately 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34,18.21, 19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49,22.97, 23.22, 24.65, 25.04, or 25.88±0.10 20, as depicted in, forexample, FIG. 19 and as found in Table 21 herein. In still anotherembodiment, a solid form provided herein, e.g., Form G, has at least 3,at least 5, at least 7, or at least 10 characteristic XPRD peaks atapproximately 7.65, 11.46, 12.51, 15.27, 15.51, 16.00, 17.34, 18.21,19.11, 19.29, 19.42, 19.84, 20.23, 21.31, 21.57, 21.79, 22.49, 22.97,23.22, 24.65, 25.04, or 25.88±0.10 20, as depicted in, for example, FIG.19 and as found in Table 21 herein. In yet another embodiment, a solidform described herein, e.g., Form G, has one, two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, twenty, or all of the characteristic XRPD peaks as set forth inTable 21.

In still another embodiment, a solid form provided herein, e.g., Form G,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 11.46, 12.51, 15.27, 16.00,19.29, 19.42, 20.23, 22.49, 22.97, or 24.65±0.1° 2θ, as depicted in, forexample, FIG. 19. In still another embodiment, a solid form providedherein, e.g., Form G, has one, two, three, four, or five characteristicXRPD peaks at approximately 11.46, 12.51, 19.29, 19.42, or 20.23±0.1°20, as depicted in, for example, FIG. 19. In still another embodiment, asolid form provided herein, e.g., Form G, has one, two, three, four, orfive characteristic XRPD peaks at approximately 11.46, 12.51, 19.29,19.42, or 20.23±0.05° 2θ, as depicted in, for example, FIG. 19.

In one embodiment described herein, is a solid form, e.g., Form G,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 20. In certainembodiments, the crystalline form exhibits a TGA thermogram comprising atotal mass loss of approximately 2% of the total mass of the sample.

In another embodiment described herein, is a solid form, e.g., Form G,having a DSC thermogram substantially as depicted in FIG. 20 comprisingan endothermic event with an onset temperature of about 173° C. and apeak maximum temperature of about 178° C.

In still another embodiment, Form G is pure. In certain embodiments,pure Form G is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, pure Form G is substantially free of FormB, Form D, or Form E. In certain embodiments, the purity of the Form Gis no less than about 95%, no less than about 96%, no less than about97%, no less than about 98%, no less than about 98.5%, no less thanabout 99%, no less than about 99.5%, or no less than about 99.9%.

Compound C, Form 1

In certain embodiments, provided herein is a solid form of Compound Cdesignated as Form 1. Form 1 is a crystalline solid form of Compound C.

In one embodiment, Form 1 of Compound C is obtained by slurryingCompound C in isoamyl alcohol/water at about a 3:1 ratio for about 1.5hours at about 55° C. The liquid of the mixture is then evaporated underflow of nitrogen and reduced pressure. In another embodiment, Form 1 ofcompound C is obtained by slurrying Compound C in ethanol/heptane at aratio of about 3:8 at RT. In still another embodiment, Form 1 ofcompound C is obtained by slurrying Compound C in ethanol/heptane at aratio of about 1:1 at RT. Form 1 can be prepared according to themethods and examples described herein.

In one embodiment, a solid form provided herein, e.g., Form 1, isfumarate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD is substantially as shown in FIG. 27a . Inanother embodiment, a solid form provided herein, e.g., Form 1, has oneor more characteristic XRPD peaks at approximately 7.58, 10.59, 11.44,11.84, 12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86,20.23, 21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93±0.1°2θ, as depicted in, for example, FIG. 27a and as found in Table 36herein. In still another embodiment, a solid form provided herein, e.g.,Form 1, has at least 3, at least 5, at least 7, or at least 10characteristic XPRD peaks at approximately 7.58, 10.59, 11.44, 11.84,12.5, 14.44, 15.45, 15.78, 16.09, 17.55, 18.92, 19.69, 19.86, 20.23,21.35, 22.04, 23.16, 23.89, 24.23, 24.67, 25.23, or 25.93±0.1° 2θ, asdepicted in, for example, FIG. 27a and as found in Table 36 herein. Inyet another embodiment, a solid form described herein, e.g., Form 1, hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, twenty, or all of thecharacteristic XRPD peaks as set forth in Table 36.

In still another embodiment, a solid form provided herein, e.g., Form 1,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 10.59, 15.45, 15.78, 16.09,18.92, 19.69, 19.86, 21.35, 23.16, or 24.23±0.1° 2θ, as depicted in, forexample, FIG. 27a . In still another embodiment, a solid form providedherein, e.g., Form 1, has one, two, three, four, or five characteristicXRPD peaks at approximately 16.09, 18.92, 19.69, 19.86, or 23.16±0.1° 2θas depicted in, for example, FIG. 27a . In still another embodiment, asolid form provided herein, e.g., Form 1, has one, two, three, four, orfive characteristic XRPD peaks at approximately 16.09, 18.92, 19.69,19.86, or 23.16±0.05° 2θ as depicted in, for example, FIG. 27 a.

In one embodiment described herein, is a solid form, e.g., Form 1,having a TGA thermograph corresponding substantially to therepresentative TGA thermogram as depicted in FIG. 28 depicts the TGA andDSC for Compound C Form 1.

FIG. 29. In certain embodiments, the crystalline form exhibits a TGAthermogram comprising a total mass loss of approximately 2% of the totalmass of the sample.

In another embodiment described herein, is a solid form, e.g., Form 1,having a DSC thermogram substantially as depicted in FIG. 28 depicts theTGA and DSC for Compound C Form 1.

FIG. 29 comprising an endothermic event with an onset temperature ofabout 167° C. and a peak maximum temperature of about 172° C.

In still another embodiment, Form 1 is pure. In certain embodiments,pure Form 1 is substantially free of other solid forms, e.g., amorphoussolid. In certain embodiments, the purity of the Form 1 is no less thanabout 95%, no less than about 96%, no less than about 97%, no less thanabout 98%, no less than about 98.5%, no less than about 99%, no lessthan about 99.5%, or no less than about 99.9%.

In another embodiment described herein, is a solid form, e.g., Form 1,having a PLM image as depicted in FIG. 30.

Compound C, Form 2

In certain embodiments, provided herein is a solid form of Compound Cdesignated as Form 2. Form 2 is a crystalline solid form of Compound C.

In one embodiment, a solid form provided herein, e.g., Form 2, isfumarate salt of Compound A, and is substantially crystalline, asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD is substantially as shown in FIG. 27b . Inanother embodiment, a solid form provided herein, e.g., Form 2, has oneor more characteristic XRPD peaks at approximately 11.52, 11.87, 15.55,16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87, 20.24, 21.35, 22.03,23.23, 23.91, 25.43, or 26.03±0.1° 2θ, as depicted in, for example, FIG.27b and as found in Table 37 herein. In still another embodiment, asolid form provided herein, e.g., Form 2, has at least 3, at least 5, atleast 7, or at least 10 characteristic XPRD peaks at approximately11.52, 11.87, 15.55, 16.04, 16.51, 17.32, 18.36, 19.00, 19.43, 19.87,20.24, 21.35, 22.03, 23.23, 23.91, 25.43, or 26.03±0.1° 2θ, as depictedin, for example, FIG. 27b and as found in Table 37 herein. In yetanother embodiment, a solid form described herein, e.g., Form 1, hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, or all of the characteristic XRPDpeaks as set forth in Table 37 herein.

In still another embodiment, a solid form provided herein, e.g., Form 1,has one, two, three, four, five, six, seven, eight, nine, or tencharacteristic XRPD peaks at approximately 11.87, 15.55, 16.04, 16.51,17.32, 19.43, 19.87, 20.24, 23.23, or 23.91±0.1° 2θ, as depicted in, forexample, FIG. 27b . In still another embodiment, a solid form providedherein, e.g., Form 1, has one, two, three, four, or five characteristicXRPD peaks at approximately 15.55, 19.43, 19.87, 20.24, or 23.23±0.1° 2θas depicted in, for example, FIG. 27b . In still another embodiment, asolid form provided herein, e.g., Form 1, has one, two, three, four, orfive characteristic XRPD peaks at approximately 15.55, 19.43, 19.87,20.24, or 23.23±0.05° 2θ as depicted in, for example, FIG. 27 b.

Amorphous Form of Freebase Compound A

In certain embodiments, provided herein is an amorphous solid form offreebase Compound A.

In one embodiment, is an amorphous solid form of freebase Compound A asindicated by X-ray powder diffraction pattern (XRPD) measurements. Inone embodiment, the XRPD is substantially as shown in FIG. 33.

In one embodiment described herein, is an amorphous solid form offreebase Compound A having a TGA thermograph corresponding substantiallyto the representative TGA and DSC thermogram as depicted in FIG. 34. Incertain embodiments, the amorphous form exhibits a TGA thermogramcomprising a total mass loss of approximately 9.3% of the total mass ofthe sample.

In still another embodiment, the amorphous solid form of Compound A ispure. In certain embodiments, pure amorphous solid form of Compound A issubstantially free of other solid forms, e.g., crystalline solids asdescribed herein. In certain embodiments, the purity is no less thanabout 95%, no less than about 96%, no less than about 97%, no less thanabout 98%, no less than about 98.5%, no less than about 99%, no lessthan about 99.5%, or no less than about 99.9%.

Pharmaceutical Compositions

The compounds described herein can be administered, for example, orally,intramuscularly, subcutaneously, intravenously, intradermally,percutaneously, intraarterially, intraperitoneally, intralesionally,intracranially, intraarticularly, intraprostatically, intrapleurally,intratracheally, intrathecally, intranasally, intravaginally,intrarectally, topically, intratumorally, peritoneally,subconjunctivally, intravesicularly, mucosally, intrapericardially,intraumbilically, intraocularly, intraorbitally, intravitreally (e.g.,by intravitreal injection), by eye drop, topically, transdermally,parenterally, by inhalation, by injection, by implantation, by infusion,by continuous infusion, by localized perfusion bathing target cellsdirectly, by catheter, by lavage, in creams, or in lipid compositions.Compounds described herein can be formulated in pharmaceuticalcompositions as provided herein suitable for oral administration. Inanother embodiment, a compound described herein can be administeredintramuscularly.

In one embodiment, compounds described herein are administered aspharmaceutical compositions capable of being administered to a subjectorally or parenterally. Pharmaceutical compositions of the compoundsdescribed herein can be prepared as oral dosage forms such as, forexample, capsules, microcapsules, tablets (coated and non-coatedtablets), granules, powders, pills, or suppositories. The compoundsdescribed herein can be formulated for topical or parenteral use wherethe compound is dissolved or otherwise suspended in a solution suitablefor injections, suspensions, syrups, creams, ointments, gels, sprays,solutions and emulsions.

Pharmaceutical compositions described herein include one or morepharmaceutically acceptable excipients such as, but not limited to:sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc,calcium phosphate or calcium carbonate, cellulose, methylcellulose,hydroxymethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,hydroxypropylstarch, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol (PEG), starch, sodiumbicarbonate, calcium citrate, magnesium stearate, sodium lauryl sulfate,sodium benzoate, sodium bisulfite, methylparaben, propylparaben, citricacid, sodium citrate or acetic acid, polyvinyl pyrroliclone, aluminumstearate), water, and cocoa butter. Uses as, for example, diluents,binders, lubricants and disintegrators of such excipients is well knownin the art.

The pharmaceutical compositions described herein include an effectiveamount of the compound described herein (e.g. Compound A, Compound B,Compound C, Compound D, or a solid form thereof). The dose of thecompound described herein can be a measure of a specific amount of thecompound (e.g. a standard dose amount) or can be measured as a functionof, for example, a patient's body weight. In one embodiment, a compounddescribed herein is administered in an amount equivalent to about 0.1,0.5, 0.75, 1, 2, 3, 4, 5, 10, 15, 20, 30, 50, 75, 100, 200, or 250mg/kg. In another embodiment, a compound described herein isadministered in an amount of about 0.1 mg/kg to about 1 mg/kg; about 0.5mg/kg to about 2 mg/kg; about 1 mg/kg to about 5 mg/kg; about 3 mg/kg toabout 10 mg/kg; about 8 mg/kg to about 15 mg/kg; or about 15 mg/kg toabout 30 mg/kg. In still another embodiment, a compound described hereinis administered in an amount less than about 100 mg/kg, less than about50 mg/kg, less than about 30 mg/kg, less than about 10 mg/kg, or lessthan about 1 mg/kg.

In one embodiment, a compound described herein is administered at anamount of about 1, 5, 10, 20, 25, 30, 50, 60, 75, 90, 100, 120, 150, or250 mg. In another embodiment, a compound described herein isadministered in an amount of about 10 mg. In still another embodiment, acompound described herein is administered in an amount of about 30 mg.In still another embodiment, a compound described herein is administeredin an amount of about 90 mg. In one embodiment, the pharmaceuticalcomposition comprising the compound described herein is administered inan amount prescribed above once per day (QD). The compound can beCompound B, or a solid form thereof (e.g. Form A, Form B, Form C, FormD, Form E, Form F, or Form G). In another embodiment, the compound is asolid form of Compound B (e.g. Form B, Form D, or Form F). In oneembodiment, the compound is Compound C or Compound C Form 1 or Form 2.In another embodiment, the compound is Compound D or a solid formdescribed herein.

In another embodiment, a compound described herein is administered at anamount of about 1 mg to about 10 mg; about 10 mg to about 30 mg; about10 mg to about 90 mg; about 30 mg to about 90 mg; or about 90 mg toabout 250 mg. In one embodiment, the compound administered is Compound Bat an amount of about 1, 10, 30, 50, 90, 100, or 150 mg. The doses of acompound described herein can be provided as a single dose (e.g. asingle tablet or capsule of the given dosage amount) or can be providedas multiple doses given over a period of time (e.g. 2 or more tablets orcapsules equating to the dosage amount). The compound can be Compound B,or a solid form thereof (e.g. Form A, Form B, Form C, Form D, Form E,Form F, or Form G). In another embodiment, the compound is a solid formof Compound B (e.g. Form B, Form D, or Form F). In one embodiment, thecompound is Compound C or Compound C Form 1 or Form 2. In anotherembodiment, the compound is Compound D or a solid form described herein.

Pharmaceutical compositions described herein can be administered oncedaily (QD); twice daily (BID), thrice daily (TID), every other day(Q2D), every three days (Q3D), or once a week. Further, doses ofpharmaceutical compositions provided herein comprising a compounddescribed herein can be administered before food (ac), after food (pc),or with food. In one embodiment, a compound described herein isadministered QD for a treatment period (a period of time where the drugis administered to a patient described herein) followed by a rest period(a period of time where the drug is not administered to a patientdescribed herein). Rest periods may include administration ofanti-cancer agents other than a compound described herein. In oneembodiment, a compound described herein is formulated for oraladministration as provided herein and is administered QD for 20-28 daysfollowed by a 3-10 day rest period. In another embodiment, the compoundis administered QD with no rest period.

Preferably a compound described herein is formulated for oraladministration. Oral administration can promote patient compliance intaking the compound (e.g. formulated as a pharmaceutical composition),thereby increasing compliance and efficacy. Oral pharmaceuticalcompositions comprising a compound described herein include, but are notlimited to, tablets (e.g. coated, non-coated and chewable) and capsules(e.g. hard gelatin capsules, soft gelatin capsules, enteric coatedcapsules, and sustained release capsules). Tablets can be prepared bydirect compression, by wet granulation, or by dry granulation. Oralpharmaceutical compositions comprising a compound described herein canbe formulated as understood in the art for delayed or prolonged release.In one embodiment, Compound B or a solid form described herein (e.g.Form B, Form D, or Form F) is formulated as a tablet or a capsule fororal administration in an amount set forth herein.

Further provided herein are compounds having the formulae:

Compounds M1, M2, M3, and M4 can be considered metabolites and/ordegradants of Compound B, including solid forms described herein. Incertain instances, such compounds can be found in compositions describedherein where such compositions have been stored for a given period oftime at a relative humidity (RH) of about 50%, 55%, 60%, 65%, 70%, 75%,80% or more. Such compounds can also be found at elevated temperaturesof about 30° C., 35° C., 40° C., 45° C., or about 50° C. In oneembodiment, compound M1, M2, M3, or M4 is found in composition describedherein where the composition comprises less than about 30 mg of CompoundB or a solid form thereof. In certain instances, such compounds arefound in compositions where the composition comprises an uncoated tabletas described herein.

In certain embodiments, compositions described herein comprisingCompound B or a solid form of Compound B described herein (e.g. Form A,Form B, Form C, Form D, Form E, Form F, or Form G) comprise less than0.01%, 0.02%, 0.03%, 0.04, 0.05, 0.1, 0.15, 0.75, 0.2, 0.225, 0.25, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% w/w of one or more of M1, M2, M3, orM4. In one embodiment, a composition described herein comprises lessthan about 0.5% w/w of one or more of M1, M2, M3, or M4.

Methods of Treating Cancer

The compounds and solid forms described herein can be administered in aneffective amount (e.g. an amount as described herein) for treatingcancer. It is to be understood that the methods described herein alsoinclude treatment with a pharmaceutical composition as described hereincomprising a compound (e.g. Compound B or a solid form thereof)described herein and one or more pharmaceutically acceptable excipients.

In one embodiment provided herein is a method of treating cancer byadministering an effective amount of Compound B as described herein to apatient having cancer. In one embodiment, Compound B is a solid form asdescribed herein (e.g. Form A, Form B, Form C, Form D, Form E, Form F,or Form G).

In another aspect provided herein Compound B, Form A can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form B can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form C can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form D can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form E can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form F can be administeredas described herein to treat a patient having a cancer as set forthherein.

In another aspect provided herein Compound B, Form G can be administeredas described herein to treat a patient having lung cancer, ovariancancer, endometrial cancer, prostate cancer, uterine cancer, or breastcancer as set forth herein.

In another aspect provided herein an amorphous non-crystalline form ofCompound A or Compound B can be administered as described herein totreat a patient having lung cancer, ovarian cancer, endometrial cancer,prostate cancer, uterine cancer, or breast cancer as set forth herein.

In another aspect provided herein is a method of treating lung cancer,ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, orbreast cancer by administering an effective amount of Compound B or asolid form as described herein to a patient having said cancer. In oneembodiment, the cancer is ovarian cancer or endometrial cancer. In oneembodiment, the cancer is breast cancer. In one embodiment of suchmethods, Compound B is a solid form as described herein (e.g. Form A,Form B, Form C, Form D, Form E, Form F, or Form G).

In a further aspect, Compound B, Form A can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form B can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form C can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form D can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form E can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form F can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, Compound B, Form G can be administered as describedherein to treat a patient having lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer asset forth herein.

In a further aspect, an amorphous non-crystalline form of Compound A orCompound B can be administered as described herein to treat a patienthaving lung cancer, ovarian cancer, endometrial cancer, prostate cancer,uterine cancer, or breast cancer as set forth herein.

Further provided herein are methods of treating breast cancer in apatient having breast cancer by administering an effective amount ofCompound B or a solid form of Compound B as described herein. In oneembodiment is a method of treating breast cancer in such a patient byadministering an effective amount of a solid form of Compound B asdescribed herein. In one embodiment, the method comprises treatingbreast cancer in a patient having breast cancer by administering to thepatient an effective amount of Compound B, Form B as described herein.In one embodiment, the method comprises treating breast cancer in apatient having breast cancer by administering to the patient aneffective amount of pure Compound B (e.g. substantially free of anothersolid form described herein, e.g. substantially free of Form D and/orForm F). In another aspect the method comprises treating breast cancerin a patient having breast cancer by administering to the patient aneffective amount of Compound B, Form D as described herein. In anotheraspect the method comprises treating breast cancer in a patient havingbreast cancer by administering to the patient an effective amount ofCompound B, Form F as described herein. In still another aspect themethod comprises treating breast cancer in a patient having breastcancer by administering to the patient an effective amount of CompoundB, Form A as described herein. In still another aspect the methodcomprises treating breast cancer in a patient having breast cancer byadministering to the patient an effective amount of Compound B, Form Cas described herein. In still another aspect the method comprisestreating breast cancer in a patient having breast cancer byadministering to the patient an effective amount of Compound B, Form Eas described herein. In still another aspect the method comprisestreating breast cancer in a patient having breast cancer byadministering to the patient an effective amount of Compound B, Form G,as described herein. In still another aspect the method comprisestreating breast cancer in a patient having breast cancer byadministering to the patient an effective amount of an amorphousnon-crystalline form of Compound B as described herein.

The compounds described herein (e.g. Compound B or a solid form thereofas described herein) can be used in the manufacture of a medicament foruse in treating breast cancer as described herein.

The methods of treating breast cancer provided herein comprise treatmentwhere the breast cancer can be hormone receptor positive breast cancer(e.g. ER+ breast cancer), HER2-positive breast cancer, HER2-negativebreast cancer, or triple negative breast cancer (TNBC).

In one embodiment, the breast cancer is HER2-negative breast cancer.HER2-negative breast cancer can be defined herein as, for example, aHER2 IHC score of 0 or 1+, or an IHC score of 2+ accompanied by anegative fluorescence, chromogenic, or silver in situ hybridization testindicating the absence of HER2-gene amplification, or a HER2/CEP17 ratioof <2.0, or local clinical guidelines. In one embodiment, the breastcancer is ER+/HER2− breast cancer. The breast cancer can be stage 0, I,II, III, or IV as understood in the art.

In another embodiment, the breast cancer is locally advanced ormetastatic breast cancer (mBC).

In one embodiment, Compound B or a solid form thereof (e.g. Form B, FormD, or Form F) can be administered as a component of adjuvant therapy. Inanother embodiment, Compound B or a solid form thereof (e.g. Form B,Form D, or Form F) can be administered as a component of neoadj uvanttherapy.

Breast cancer patients described herein may be premenopausal beforetreatment with a compound or solid form as described herein. Breastcancer patients described herein may be postmenopausal before treatmentwith a compound or solid for as described herein.

The methods provided herein include administering an effective amount ofCompound B or a solid form as described herein to the patient at anamount as set forth herein. The effective amount can be, for example, anamount of about 10 mg, 30 mg, 50 mg, 90 mg, 100 mg, 125 mg, or 250 mg.In one embodiment of the methods provided herein, Compound B or a solidform described herein is administered orally. In one embodiment,Compound B or a solid form thereof is administered as a tablet (e.g. acoated or non-coated tablet). In another embodiment, Compound B or asolid form thereof is administered as a capsule. Thus, provided hereinare compositions suitable for administration to a breast cancer patientwhere such compositions comprise an amount of Compound B or a solid formdescribed herein of about 10 mg, 30 mg, 50 mg, 90 mg, 100 mg, 125 mg, or250 mg in a tablet or capsule as set forth herein. When administered inaccordance with the methods provided herein, Compound B or a solid formthereof can be pure as described herein.

Patients of the methods described above may have had previous treatmentwith one or more anti-cancer agents or radiation therapy. For example,in one embodiment, a patient may have been previously treated (e.g. witha 1 L, 2 L, 3 L or more line therapy) with doxorubicin, pegylatedliposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel,docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin,vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib,methotrexate, anastrozole, exemestane, toremifene, letrozole, tamoxifen,4-hydroxy tamoxifen, raloxifene, droloxifene, trioxifene, keoxifene,ftutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin,leuprolide, pegfilgrastim, filgrastim, or venetoclax.

In another embodiment, a patient may have been previously treated (e.g.with a 1 L, 2 L, 3 L or more line therapy) with an AKT inhibitor, aCDK4/6 inhibitor, a PARP inhibitor, or an aromatase inhibitor. In oneembodiment, the AKT inhibitor is ipatasertib (GDC-0068). In oneembodiment, the CDK4/6 inhibitor is abemaciclib, ribociclib, orpalbociclib. In certain instances, a patient may have been previouslytreated with: (1) abemaciclib, ribociclib, or palbociclib; (2)ipatasertib; (3) everolimus or fulvestrant; (4) -trastuzumab emtansine,trastuzumab, pertuzumab, or atezolizumab; or (5) alemtuzumab,bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or acombination thereof. Patients described herein may have had surgeryprior to treatment with Compound B or the solid form thereof.

In another embodiment, a patient herein may be refractory to one or moreanti-cancer therapies. For example, a patient herein may be refractoryto aromatase inhibitors. In another example, a patient herein may berefractory to a selective estrogen receptor degrader (SERD) such as, forexample, fulvestrant. In still another example, a patient may berefractory to one or more endocrine therapies such as, clomifene,toremifene, raloxifene, anordrin, bazedoxifene, broparestrol,cyclofenil, lasofoxifene, ormeloxifene, acolbifene, elacestrant,brilanestrant, clomifenoxide, droloxifene, etacstil, or ospemifene. Inanother embodiment, a patient may be refractory to abemaciclib,anastrozole, exemestane, fulvestrant, goserelin, letrozole, leuprorelin,megestrol, palbociclib, tamoxifen, or toremifene. In another example, apatient may be refractory to treatment with trastuzumab emtansine,trastuzumab, pertuzumab, atezolizumab, pembrolizumab, durvalumab,avelumab, or nivolumab.

The compounds described herein can also be used in methods comprisinginhibiting ERalpha in a patient. Such methods comprise administering anamount of a compound described herein (e.g. Compound A or Compound B,including solid forms thereof as described herein) to the patient.

Combination Therapies

The compounds and solid forms described herein can be administered incombination with one or more anti-cancer agents. Administration “incombination” as set forth herein includes sequential administration (inany order) of a compound described herein and one or more anti-cancertherapies as well as simultaneous administration. Accordingly, providedherein are methods of treating breast cancer in a patient having breastcancer, such methods comprising administering Compound B or a solid formas described herein in combination with one or more additionalanti-cancer therapies. In one embodiment, the anti-cancer therapycomprises doxorubicin, pegylated liposomal doxorubicin, epirubicin,paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil,cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine,gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole,exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen,raloxifene, droloxifene, trioxifene, keoxifene, ftutamide, nilutamide,bicalutamide, lapatinib, vinblastine, goserelin, leuprolide,pegfilgrastim, filgrastim, or venetoclax.

In one embodiment provided herein is a method of treating breast cancerin a patient having breast cancer by administering an effective amountof Compound B or a solid form as described herein in combination withdoxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel,albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide,cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine,ixabepilone, eribulin, olaparib, methotrexate, anastrozole, exemestane,toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen, raloxifene,droloxifene, trioxifene, keoxifene, ftutamide, nilutamide, bicalutamide,lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim,filgrastim, or venetoclax.

In another aspect provided herein is a method of treating breast cancerin a patient having breast cancer by administering an effective amountof Compound B or a solid form as described herein in combination withpaclitaxel, albumin-bound paclitaxel, methotrexate, anastrozole,exemestane, toremifene, letrozole, tamoxifen, 4-hydroxy tamoxifen,raloxifene, droloxifene, trioxifene, keoxifene, or venetoclax. In stillanother aspect provided herein is a method of treating breast cancer ina patient having breast cancer by administering an effective amount ofCompound B or a solid form as described herein in combination withfulvestrant, paclitaxel, albumin-bound paclitaxel, clomifene,toremifene, raloxifene, anordrin, bazedoxifene, broparestrol,cyclofenil, lasofoxifene, ormeloxifene, acolbifene, elacestrant,brilanestrant, clomifenoxide, droloxifene, etacstil, or ospemifene.

In still another aspect provided herein is a method of treating breastcancer in a patient having breast cancer by administering an effectiveamount of Compound B or a solid form as described herein in combinationwith a CDK4/6 inhibitor, a PARP inhibitor, or an aromatase inhibitor.

In a further aspect provided herein is a method of treating breastcancer in a patient having breast cancer as described herein where themethod comprises administering an effective amount of Compound B or asolid form as described herein in combination with a CDK4/6 inhibitorwhere the CDK4/6 inhibitor is abemaciclib, ribociclib, or palbociclib.In a preferred embodiment, the method comprises administering Compound Bor a solid form as described herein in combination with palbociclib. Instill another embodiment, the method comprises administering Compound Bor a solid form as described herein in combination with abemaciclib orribociclib. In another aspect provided herein is a kit comprising (i)Compound B or a solid form thereof in a unit dosage form; (ii) a CDK4/6inhibitor (e.g. palbociclib) in a second unit dosage form; and acontainer containing each dosage form.

The dose of abemaciclib may be 50 mg to 500 mg daily, or 150 mg to 450mg daily and the dosing can be daily in 28 day cycles or less than 28days per 28 day cycles such as 21 days per 28 day cycle or 14 days per28 day cycle or 7 days per 28 day cycles. In one embodiment, abemaciclibis dosed once daily or preferably on a bid schedule where dosing isoral. In the case of bid dosing, the doses can be separated by 4 hours.8 hours or 12 hours. In certain embodiments, abemaciclib is dosed at 150mg orally bid where each dose is administered about 12 hr apart. Incertain embodiments, the dose of abemaciclib is administered inaccordance with a package insert.

The dose of ribociclib may be 200 mg to 1,000 mg daily; or 250 mg to 750mg daily and the dosuig can be daily in 28 day cycles or less than 28days per 28 day cycles such as 21 days per 28 day cycle or 14 days per28 day cycle or 7 days per 28 day cycles. In one embodiment, ribociclibis dosed once daily where dosing is oral. In certain embodiments, thedose of ribociclib is administered in accordance with a package insert.

The dose of palbociclib may be 25 mg to 250 mg daily or 50 mg to 125 mgdaily or from 75 mg to 125 mg daily or 75 mg daily to 100 mg daily or125 mg daily. The dosing can be daily in 28 day cycles or less than 28days per 28 day cycles such as 21 days per 28 day cycle or 14 days per28 day cycle or 7 days per 28 day cycles. In one embodiment, palbociclibis dosed once daily where dosing is oral. In certain embodiments, thedose of palbociclib is administered in accordance with a package insert.

In another aspect provided herein the methods described herein compriseadministering an effective amount of Compound B or a solid form asdescribed herein in combination with an aromatase inhibitor (AI), wherethe AI is letrozole, anastrozole, exemestane, or testolactone.

In yet another aspect provided herein is a method of treating breastcancer in a patient having breast cancer by administering an effectiveamount of Compound B or a solid form as described herein in combinationwith a cancer immunotherapy (e.g. an antibody). In one embodiment,Compound B or a solid form as described herein is administered incombination with trastuzumab emtansine, trastuzumab, pertuzumab,atezolizumab, pembrolizumab, durvalumab, avelumab, or nivolumab, or acombination thereof. In one embodiment, Compound B or a solid form asdescribed herein is administered in combination with a cancerimmunotherapy comprising PD-1 or PD-L1 inhibitor, where the cancerimmunotherapy is atezolizumab, pembrolizumab, or nivolumab.

Administration of a compound described herein (e.g. Compound B or asolid form as described herein) results in patients having adverseeffects (AEs) characterized as Grade 2 or lower. In one embodiment, apatient administered Compound B or a solid form as described herein hasGrade 2 or lower AEs.

Examples

The following Examples are presented by way of illustration, notlimitation.

Synthesis of Compounds described herein. All reagents and solvents werepurchased from commercial suppliers and used with no additionalpurification. Anhydrous solvent (dichloromethane) was utilized.Commercially available solvents were not further purified.

All reactions were carried out in screw-cap vials equipped with a Teflonsepta under a nitrogen atmosphere.

Flash column chromatography was performed using a teledyne IscoCombiFlash® Rf instrument with pre-packed RediSepRf Gold silicacartridges.

Unless otherwise indicated, reported yields are for isolated materialand are corrected for residual solvents.

Compounds were characterized by one or more of ¹H NMR, ¹³C NMR, meltingpoint and HRMS, and HPLC analysis (e.g., for confirmation of purity).

¹H, and ¹³C Nuclear Magnetic Resonance Spectra were recorded on a Bruker400 MHz instrument at ambient temperature. All ¹H NMR spectra weremeasured in parts per million (ppm) relative to residual chloroformsignal (7.26 ppm) or dimethyl sulfoxide (2.50 ppm) in the deuteratedsolvent unless otherwise stated. Data for ¹H NMR are reported asfollows: chemical shift, multiplicity (br=broad signal,overlap=overlapping, s=singlet, d=doublet, t=triplet, q=quartet,p=pentet, m=multiplet), coupling constants and integration. All ¹³C NMRspectra are reported in ppm relative to deuterochloroform (77.06 ppm) ordeuterated dimethyl sulfoxide (39.53 ppm), and were obtained withcomplete ¹H decoupling unless otherwise stated. HPLC analyses wereperformed on an Agilent 1260 Infinity HPLC system with a UV detector at220 nm using an Ace Super C18 column. Melting points were obtained usinga Buchi B-540 Melting Point Apparatus and are uncorrected. Highresolution mass spectrometry (HRMS) data was acquired on a ThermoScientific Orbitrap Fusion mass spectrometer.

Examples 1-3: Indole Alkylation

Indole alkylation was done by the sequence of Boc protection (Example1), sulfamide formation (Example 2), and indole alkylation (Example 3)

Example 1: Boc Protection Example 1: Boc Protection General ReactionScheme

Boc protection was done according to the following general reactionscheme where R_(A) and R_(B) correspond to the various functional groupsin the following Example 1 protection reactions, and wherein theasterisks represent a chiral center:

Example 1A: Preparation of tert-butyl(S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate

General reaction scheme 1 above was performed as follows. To a slurry of(S)-2-amino-2-(4-methoxyphenyl)ethan-1-ol hydrochloride (1.04 g, 5.10mmol, 100 mol %) in THF (4.4 mL) was added Boc₂O (1.21 mL, 5.61 mmol,110 mol %), NaHCO₃ (451 mg, 5.10 mmol, 100 mol %), and water (4.4 mL) atrt. The solution was stirred at rt for 18 h, and extracted with iPrOAc(20 mL×2). The organic layer was washed with saturated brine (20 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure toprovide the product without further purification. Example 1A yield isreported are corrected based on residual solvent from ¹H NMR. Thereaction yielded tert-butyl(S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate (1.36 g, 100% yield)as a white solid. mp: 139.0-139.9° C.; FTIR (neat, cm⁻¹) 3370, 2984,2837, 1681, 1613, 1512, 1461; ¹H NMR (400 MHz, CDCl₃): δ 7.24-7.20 (m,2H), 6.92-6.86 (m, 2H), 5.10 (d, J=7.2 Hz, 1H), 4.72 (br, 1H), 3.82 (t,J=5.6 Hz, 2H), 3.80 (s, 3H), 2.35 (br, 1H), 1.43 (s, 9H); ¹³C NMR (100MHz, CDCl₃): δ 159.1, 156.2, 131.6, 127.7, 114.2, 80.0, 66.8, 56.4,55.3, 28.4.

Example 1B: Preparation of tert-butyl(R)-(1-cyclopropyl-2-hydroxyethyl)carbamate

The general reaction scheme as per Example 1A above was performed with(R)-2-amino-2-cyclopropylethan-1-ol (1.16 g, 11.5 mmol, 100 mol %) toyield tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (2.31 g,100% yield) as a white solid. mp: 70.0-70.8° C.; FTIR (neat, cm⁻¹) 3358,2974, 2937, 1682, 1521, 1366; ¹H NMR (400 MHz, CDCl₃): δ 4.80 (br, 1H),3.80 (ddd, J=10.8, 6.8, 3.2 Hz, 1H), 3.67 (ddd, J=10.8, 6.0, 4.8 Hz,1H), 2.94 (dtd, J=9.6, 6.4, 3.2 Hz, 1H), 2.81 (br, 1H), 1.45 (s, 9H),0.85 (dtt, J=9.6, 8.0, 4.8 Hz, 1H), 0.60-0.47 (m, 2H), 0.44-0.25 (m,2H); ¹³C NMR (100 MHz, CDCl₃): δ 156.6, 79.7, 66.3, 57.9, 28.4, 13.0,3.3, 2.9.

Example 1C: Preparation of tert-butyl((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate

The general reaction scheme as per Example 1A above was performed with(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (5.15 g, 34.5 mmol, 100 mol %)to yield tert-butyl((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (8.61 g, 100%yield) as a white solid. mp: 67.3-68.4° C.; FTIR (neat, cm⁻¹) 3428,3350, 2983, 2933, 1688, 1509; ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.26 (m,1H), 7.26-7.18 (m, 3H), 5.17 (br, 1H), 5.05 (br, 1H), 4.57 (ddd, J=7.2,4.8, 2.0 Hz, 1H), 3.12 (dd, J=16.8, 5.2 Hz, 1H), 2.91 (dd, J=16.8, 2.4Hz, 1H), 2.31 (d, J=4.8 Hz, 1H), 1.50 (s, 9H); ¹³C NMR (100 MHz, CDCl₃):δ 156.3, 140.9, 139.9, 128.2, 127.1, 125.3, 124.5, 79.9, 73.6, 58.9,39.4, 28.4.

Example 1D: Preparation of tert-butyl(S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate

The general reaction scheme as per Example 1A above was performed with(S)-2-amino-2-(3-fluorophenyl)ethan-1-ol (1.36 g, 8.73 mmol, 100 mol %)to yield tert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate(2.23 g, 100% yield) as a white solid. mp: 106.5-107.9° C.; FTIR (neat,cm⁻¹) 3251, 3059, 2977, 2901, 1671, 1587, 1543; ¹H NMR (400 MHz, CDCl₃):δ 7.33 (ddd, J=7.6, 7.6, 6.0 Hz, 1H), 7.12-7.07 (m, 1H), 7.05-6.95 (m,2H), 5.24 (br, 1H), 4.77 (br, 1H), 3.93-3.77 (m, 2H), 2.02 (br, 1H),1.44 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 163.0 (d, ¹J_(CF)=246 Hz),156.0, 142.5, 130.2 (d, ³J_(CF)=9 Hz), 122.2 (d, ⁴J_(CF)=3 Hz), 114.5(d, ²J_(CF)=21 Hz), 113.6 (d, ²J_(CF)=21 Hz), 80.2, 66.2, 56.3, 28.3;¹⁹F NMR (CDCl₃, 376 MHz): δ −112.4.

Example 1E: Preparation of(S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate

The general reaction scheme as per Example 1A above was performed with(S)-2-amino-2-(3-(trifluoromethyl)phenyl)ethan-1-ol hydrochloride (1.00g, 4.12 mmol, 100 mol %) to yield(S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.26 g, 100% yield) asa white solid. mp: 50.3-52.5° C.; FTIR (neat, cm¹⁾ 3368, 3254, 2979,2939, 1691, 1510, 1453, 1333; ¹H NMR (400 MHz, CDCl₃): δ 7.59-7.54 (m,2H), 7.53-7.45 (m, 2H), 5.31 (d, J=6.4 Hz, 1H), 4.83 (br, 1H), 3.92(ddd, J=11.2, 6.8, 4.0 Hz, 1H), 3.88-3.79 (m, 1H), 1.94 (br, 1H), 1.43(s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 156.1, 141.1, 130.9 (q, ²J_(CF)=32Hz), 130.1, 129.0, 124.3 (q, ³J_(CF)=4 Hz), 124.1 (q, ¹J_(CF)=270 Hz),123.4 (q, ³J_(CF)=4 Hz), 80.3, 65.8, 56.3, 28.2; ¹⁹F NMR (CDCl₃, 376MHz): δ −62.6. Example 2: Sulfamidate Formation

Example 2: Sulfamidate Formation General Reaction Scheme

Sulfamidate formation was done according to the following generalreaction scheme where R_(A) and R_(B) correspond to the variousfunctional groups in the following Example 2 reactions, and wherein theasterisks represent a chiral center:

Example 2A: Preparation of tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

General reaction scheme 2 above was performed as follows. To a cold(−40° C.) solution of SOCl₂ (10.9 mL, 149 mmol, 250 mol %) in CH₂Cl₂(60.0 mL) was added a solution of tert-butyl(R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (15.0 g, 59.7 mmol, 100 mol%) in CH₂Cl₂ (60.0 mL) over 60 min at −40° C. Pyridine (25.3 mL, 313mmol, 525 mol %) was then added to the reaction mixture over 30 min at−40° C. The reaction mixture was stirred at −40° C. for 2 h, solventswapped to CH₂Cl₂/iPrOAc (1:1) mixture, filtered. The filtrate waswashed with saturated brine solution (20 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The residue was dissolved inCH₃CN (60.0 mL) at 0° C. NaIO₄ (14.0 g, 65.7 mmol, 110 mol %), RuCl₃(61.9 mg, 0.298 mmol, 0.5 mol %), and water (60.0 mL) were added intothe reaction mixture at 0° C. and stirred for 15 min. The reactionmixture was then warmed to room temperature and stirred at roomtemperature for 2 h, extracted with iPrOAc (20 mL), washed withsaturated NaHCO₃ solution (15 mL), saturated brine solution (15 mL),dried (Na₂SO₄), filtered, purified by chromatography on SiO₂. Specificgradient used for each sample is included in the characterization data.All the yields reported are corrected based on residual solvent from ¹HNMR. Reaction 2A yielded tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (18.7 g,56% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH in CH₂Cl₂.mp: 134.4-135.0° C.; FTIR (neat, cm⁻¹) 3261, 2979, 2903, 1712, 1673,1540; ¹H NMR (400 MHz, CDCl₃): δ 7.38-7.20 (m, 5H), 4.49-4.40 (m, 2H),4.35-4.28 (m, 1H), 3.37 (dd, J=14.0, 4.0 Hz, 1H), 2.98-2.87 (m, 1H),1.56 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 148.5, 135.2, 129.5, 129.1,127.5, 85.6, 68.8, 58.6, 37.9, 28.0.

Example 2B: Preparation of tert-butyl(S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(2-hydroxy-1-phenylethyl)carbamate (10.0 g, 42.1 mmol,100 mol %) to yield compound tert-butyl(S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.23 g,42% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH in CH₂Cl₂.mp: 144.3-145.0° C.; FTIR (neat, cm⁻¹) 2976, 1722, 1458, 1377; ¹H NMR(400 MHz, CDCl₃): δ 7.44-7.35 (m, 5H), 5.28 (dd, J=6.4, 4.0 Hz, 1H),4.87 (dd, J=9.2, 6.4 Hz, 1H), 4.39 (dd, J=9.2, 4.4 Hz, 1H), 1.42 (s,9H); ¹³C NMR (100 MHz, CDCl₃): δ 148.3, 137.0, 129.2, 129.1, 126.2,85.5, 71.8, 60.8, 27.8.

Example 2C: Preparation of tert-butyl(S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(2-hydroxy-1-(4-methoxyphenyl)ethyl) carbamate (1.45 g,5.42 mmol, 100 mol %) to yield compound tert-butyl(S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(1.05 g, 59% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH inCH₂Cl₂. mp: 151.6-153.0° C.; FTIR (neat, cm⁻¹) 2979, 2933, 2838, 1721,1636, 1510, 1457; ¹H NMR (400 MHz, CDCl₃): δ 7.37-7.32 (m, 2H),6.95-6.90 (m, 2H), 5.24 (dd, J=6.8, 4.4 Hz, 1H), 4.84 (dd, J=9.2, 6.8Hz, 1H), 4.39 (dd, J=9.2, 4.4 Hz, 1H), 3.82 (s, 3H), 1.44 (s, 9H); ¹³CNMR (100 MHz, CDCl₃): δ 160.2, 148.3, 128.9, 127.7, 114.6, 85.5, 72.0,60.5, 55.4, 27.9.

Example 2D: Preparation of tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (R)-(1-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 100mol %) to yield compound tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.85 g,57% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH in CH₂Cl₂.FTIR (neat, cm⁻¹) 3245, 2982, 1719, 1402, 1329; ¹H NMR (400 MHz, CDCl₃):δ 4.66 (dd, J=9.2, 6.0 Hz, 1H), 4.41 (qdd, J=6.4, 6.0, 2.8 Hz, 1H), 4.19(dd, J=9.2, 2.8 Hz, 1H), 1.54 (s, 9H), 1.50 (d, J=6.4 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃): δ 148.5, 85.4, 71.4, 53.8, 28.0, 18.3.

Example 2E: Preparation of tert-butyl(R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (R)-(1-hydroxy-3-methylbutan-2-yl)carbamate (5.00 g, 24.6mmol, 100 mol %) to yield compound tert-butyl(R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.93 g,60% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH in CH₂Cl₂.mp: 104.8-105.8° C.; ¹H NMR (400 MHz, CDCl₃): δ 4.55 (dd, J=9.6, 6.4 Hz,1H), 4.38 (dd, J=9.6, 2.0 Hz, 1H), 4.17 (ddd, J=6.4, 5.2, 1.6 Hz, 1H),2.24 (qqd, J=6.8, 6.8, 5.2 Hz, 1H), 1.53 (s, 9H), 1.00 (d, J=6.8 Hz,3H), 0.95 (d, J=6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 149.1, 85.3,67.0, 62.0, 30.0, 27.9, 18.0, 16.4.

Example 2F: Preparation of tert-butyl(R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (2.31 g, 11.5mmol, 100 mol %) to yield tert-butyl(R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.36g, 45% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH inCH₂Cl₂. mp: 52.7-55.7° C.; FTIR (neat, cm⁻¹) 2977, 1734, 1460, 1363; ¹HNMR (400 MHz, CDCl₃): δ 4.64 (dd, J=9.2, 6.0 Hz, 1H), 4.40 (dd, J=8.8,2.0 Hz, 1H), 3.77 (ddd, J=9.2, 6.0, 2.0 Hz, 1H), 1.54 (s, 9H), 1.35-1.23(m, 1H), 0.74-0.65 (m, 2H), 0.63-0.54 (m, 1H), 0.29-0.20 (m, 1H); ¹³CNMR (100 MHz, CDCl₃): δ 148.9, 85.3, 71.1, 61.6, 27.9, 14.3, 4.4, 1.7.

Example 2G: Preparation of tert-butyl(3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl ((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (9.12g, 36.6 mmol, 100 mol %) to yield tert-butyl(3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3(3aH)-carboxylate2,2-dioxide (7.50 g, 66% yield) as a white solid. Column Gradient: 0 to5% CH₃OH in CH₂Cl₂. mp: 134.2-135.0° C.; FTIR (neat, cm¹) 2988, 2937,1732, 1462, 1375; ¹H NMR (400 MHz, CDCl₃): δ 7.62-7.57 (m, 1H),7.39-7.24 (m, 3H), 5.71 (d, J=5.6 Hz, 1H), 5.50 (dt, J=6.0, 3.2 Hz, 1H),3.38 (d, J=3.2 Hz, 1H), 1.62 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 149.6,138.4, 137.9, 129.9, 128.4, 126.2, 125.2, 85.7, 82.2, 65.0, 36.5, 28.0.

Example 2H: Preparation of tert-butyl(S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(2-hydroxypropyl)carbamate (6.25 g, 35.7 mmol, 100 mol %)to yield compound tert-butyl(S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (6.10 g,72% yield) as a white solid. Column Gradient: 0 to 5% CH₃OH in CH₂Cl₂.mp: 116.9-118.2° C.; FTIR (neat, cm¹) 3370, 2956, 2938, 2837, 1681,1512, 1461, 1366; ¹H NMR (400 MHz, CDCl₃): δ 5.00-4.90 (m, 1H), 4.06(dd, J=9.6, 5.6 Hz, 1H), 3.63 (dd, J=9.6, 9.2 Hz, 1H), 1.56 (d, J=6.4Hz, 3H), 1.53 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 148.6, 85.3, 76.2,51.7, 27.9, 18.0.

Example 21: Preparation of tert-butyl(S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.45 g,5.68 mmol, 100 mol %) to yield tert-butyl(S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(0.702 g, 39% yield) as a white solid. Column Gradient: 0 to 50% iPrOAcin Heptane. mp: 112.9-114.3° C.; FTIR (neat, cm⁻¹) 2976, 1722, 1636,1594, 1458; ¹H NMR (400 MHz, CDCl₃): δ 7.44-7.36 (m, 1H), 7.24-7.18 (m,1H), 7.17-7.11 (m, 1H), 7.11-7.05 (m, 1H), 5.28 (dd, J=6.8, 3.6 Hz, 1H),4.88 (dd, J=9.2, 6.8 Hz, 1H), 4.39 (dd, J=9.2, 3.6 Hz, 1H), 1.47 (s,9H); ¹³C NMR (100 MHz, CDCl₃): δ 163.2 (d, ¹J_(CF)=246 Hz), 148.2, 139.6(d, ³J_(CF)=7 Hz), 131.1 (d, ³J_(CF)=8 Hz), 121.8 (d, ⁴J_(CF)=3 Hz),116.2 (d, ²J_(CF)=21 Hz), 113.4 (d, ²J_(CF)=22 Hz), 86.0, 71.6, 60.2 (d,⁴J_(CF)=3 Hz), 27.9; ¹⁹F NMR (CDCl₃, 376 MHz): δ −111.0.

Example 2J: Preparation of tert-butyl(S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(1-(3-fluorophenyl)-2-hydroxyethyl)carbamate (1.00 g,3.28 mmol, 100 mol %) to yield tert-butyl(S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (0.528 g, 44% yield) as a white solid. Column Gradient: 0 to50% iPrOAc in Heptane. mp: 92.0-92.6° C.; FTIR (neat, cm¹) 2989, 1720,1463, 1373, 1325; ¹H NMR (400 MHz, CDCl₃): δ 7.70-7.61 (m, 3H),7.61-7.55 (m, 1H), 5.35 (dd, J=6.8, 4.0 Hz, 1H), 4.92 (dd, J=9.2, 6.8Hz, 1H), 4.41 (dd, J=9.2, 3.6 Hz, 1H), 1.46 (s, 9H); ¹³C NMR (100 MHz,CDCl₃): δ 148.2, 138.2, 131.8 (q, ²J_(CF)=32 Hz), 130.1, 129.4, 126.1(q, ³J_(CF)=4 Hz), 123.7 (q, ¹J_(CF)=270 Hz), 123.4 (q, ³J_(CF)=4 Hz),86.2, 71.4, 60.2, 27.8; ¹⁹F NMR (CDCl₃, 376 MHz): δ −62.8.

Example 2K: Preparation of tert-butyl(S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide

The general reaction scheme as per Example 2A above was performed withtert-butyl (S)-(3-hydroxy-1-phenylpropyl)carbamate (2.00 g, 7.96 mmol,100 mol %) to yield tert-butyl(S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (1.26 g, 51%yield) as a white solid. Column Gradient: 0 to 50% iPrOAc. mp:128.6-129.9° C.; FTIR (neat, cm⁻¹) 2986, 1727, 1449, 1367; ¹H NMR (400MHz, DMSO-d₆) (94:6 mixture of rotamers): δ 7.48-7.35 (m, 4H), 7.35-7.23(m, 1H), 5.65 (dd, J=4.4, 4.4 Hz, 0.94H), 5.53 (dd, J=11.2, 4.4 Hz,0.06H), 4.70 (ddd, J=10.4, 7.2, 2.8 Hz, 0.94H), 4.51 (ddd, J=8.8, 4.4,4.4 Hz, 0.06H), 4.40 (ddd, J=10.4, 10.4, 6.8 Hz, 1H), 2.80-2.68 (m, 1H),2.66-2.56 (m, 1H), 1.41 (s, 8.46H), 1.12 (s, 0.54H); ¹³C NMR (100 MHz,DMSO-d₆) (rotamers): δ 155.1, 143.0, 128.4 (128.6), 127.0 (127.3), 126.3(125.4), 78.1 (84.3), 73.6 (70.9), 50.5 (60.0), 36.0, 28.2 (27.4).

Example 3: Indole Alkylation

Chiral tryptamines are frequently encountered in pharmacology due totheir significant biological activities in the central nervous system.In addition, the chiral tryptamine moiety serves as synthetic precursorof many medicinally important indole alkaloids and found in numerousbiologically active natural products and pharmaceuticals.

In particular, stereocontrolled synthesis oftetrahydro-β-carboline-containing compounds such as those describedherein often relies on diastereoselective Pictet-Spengler reaction,which in turn requires enantiomerically pure tryptamines as startingmaterial. The latter is typically prepared in a non-stereoselectivemanner via a multistep sequence involving hazardous nitroalkanereagents. Therefore, the development of a simple regioselectivealkylation approach which involves readily available non-protectedindoles as nucleophiles and chiral amine-derived electrophiles, such aschiral aziridines and cyclic sulfamidates, provided a convenient accessto these valuable chiral scaffolds.

Aziridine electrophiles have been applied to provide C³-selectivealkylation under Lewis acidic conditions; however, this method is onlyapplicable to the synthesis of f-substituted tryptamines as thedisplacement occurs preferentially at the more substituted carbon.Discovered herein, low order cuprate of indoles in combination withchiral cyclic sulfamidates successfully provided a practical access toboth α- and β-substituted chiral tryptamines having highregioselectivity.

It was found that the reaction with chiral aziridines as theelectrophile always led to a mixture of α- and β-substituted tryptamineswhile reaction with cyclic sulfamidates as the electrophileunambiguously reacted to displace C—O bond.

Contrary to the literature precedence suggesting preferential alkylationat the C³-position when Grignard reagents were used as base, initialattempts resulted in lower than expected yields and poorsite-selectivity. Without being bound by any particular theory, softerindole nucleophiles were tried as they would likely prefer to react ascarbon-centered nucleophile. Various additives including Cu and Zn saltswere surveyed. Interestingly, a mixed halide system such as MeMgCl incombination with CuBr or CuI, or MeMgBr in combination with CuCl wasmuch less efficient than the chloride-only system. Other copper salts,such as CuCl₂, CuCN, CuTC, or Cu(SCN) were also inferior to CuCl.

entry base/additive/temperature isolated yield C³/N^(1 b)  1MeMgCl/None/−10° C. 14% 31/69  2 MeMgCl/CuCl/−10° C. 66% 95/5  3MeMgCl/CuBr/−10° C. 37% 95/5  4 MeMgCl/CuI/−10° C. 26% 90/10  5^(c)MeMgCl/CuCl/−10° C. 38% 67/33  6 MeMgCl/ZnCl₂/−10° C. 38% 22/78  7MeMgCl/ZnBr₂/−10° C. 28% 37/63  8 MeMgBr/CuCl/−10° C. 26% 45/54  9PhMgCl/CuCl/−10° C. 66% 96/4 10 MeLi/CuCl/−10° C. N.D. 11/89 11MeMgCl/CuCl/−40° C. N.D. 42/58 12^(d) MeMgCl/CuCl/−20° C. 76% 97/3 13MeMgCl/CuCl/0 °C. 65% 95/5 product isolated yield C³/N¹ ratio^(b)

6a 76% (>99% ee) 97:3

6b 6c 6d 6e 6f R = Me Ph Cl OMe CF₃ 73% 82% 60% 92% 47% 95:5 97:3 96:497:3 96:4

6g 68% 97:3

6h 6i R = Me Ph 71% 51% 99:1 98:2

6j  8% 98:2

A catalytic amount of CuCl was not tolerated and resulted in significantdecrease in yield and selectivity. Notably, a reversal ofregioselectivity was observed when zinc halides were used instead ofCuCl (see above). The same was true when MeLi was used as base insteadof MeMgCl, while the use of other Grignard reagent was well-tolerated.The effect of reaction temperature was evaluated and established thatthe displacement reaction performed optimally at around −20° C. At below−30° C., a significant drop in regioselectivity was observed presumablydue to the incomplete cuprate formation.

The Cu-mediated indole alkylation tolerated a variety of substitutionboth on the indole nucleophile as well as on the cyclic sulfamidateproviding the C³-alkylated indole products in moderate to good yield andexcellent regioselectivity. For instance, indoles with eitherelectron-donating or electron-withdrawing substituents participated inthe reaction well (Exemplary compounds 6b-6g above), and stericallydemanding substrates also worked reasonably well (Exemplary compounds 6hand 6i above).

On the other hand, azaindoles appear to be possible poor substrates.Under standard reaction conditions, 6-azaindole provided only 8% of thealkylation product albeit with comparable regioselectivity (see e.g.exemplary compound 6j above). Other azaindoles such as indazole and7-azaindole failed to produce any desired alkylated products

A variety of sulfamidates were tested in the reaction successfully. Botharyl- and alkyl-substituted sulfamidates, prepared in two step sequencefrom the corresponding amino alcohols, were converted smoothly to therespective α-substituted chiral tryptamines. Similarly, 6-memberedcyclic sulfamidate also participated in the alkylation well producing ahomologated tryptamine in good yield and regioselectivity. Thisalkylation process can be also applied to get access to β-substituted,and α,β-disubstituted tryptamines (see exemplary compounds 6s and 6tabove). In these cases, the indole nucleophile added to thecorresponding cyclic sulfamidate with the inversion of stereochemistryat the carbon bearing oxygen with complete stereospecificity. Theutility of this alkylation process was demonstrated as provided herein.

Example 3: Indole Alkylation General Reaction Scheme

Indole alkylation was done according to the following general reactionscheme where R_(A) and R_(B) correspond to the various functional groupsin the following Example 3 reactions, and wherein the asterisksrepresent a chiral center:

Example 3A: Preparation of tert-butyl(R)-(1-(1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

General reaction scheme 3 above was performed as follows. To a cold (0°C.) mixture of indole (280 mg, 2.39 mmol, 150 mol %), and CuCl (193 mg,1.95 mmol, 130 mol %) in CH₂Cl₂ (3.0 mL) was added MeMgCl (3.0 M in THF,0.65 mL, 1.95 mmol, 130 mol %) over 10 min at 0° C. The reaction mixturewas stirred at 0° C. for 1 h and cooled to −20° C. A solution oftert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(500 mg, 1.60 mmol, 100 mol %) in CH₂Cl₂ (2.0 mL) was added into thereaction mixture over 30 min at −20° C. The reaction mixture was thenstirred at −20° C. for 18 h, quenched with 10% aqueous citric acid (5.0mL) at 0° C., filtered, extracted with CH₂Cl₂ (10.0 mL×2), washed withsaturated brine (20.0 mL×2), dried (Na₂SO₄), filtered, purified bychromatography on SiO₂. Specific gradient used for each sample isincluded in the characterization data. All the yields reported arecorrected based on residual solvent from ¹H NMR. Reaction 3A yieldedtert-butyl (R)-(1-(1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (424 mg,76% yield) as a white solid. The C³/N¹ ratio was 97:3. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 152.1-153.2° C.; FTIR (neat, cm⁻¹) 3418,3402, 3376, 2974, 2911, 1684, 1522; ¹H NMR (400 MHz, DMSO-d₆) (85:15mixture of rotamers): δ 10.78 (br, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.32 (d,J=8.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.19-7.10 (m, 4H), 7.05 (ddd, J=8.4,7.2, 1.2 Hz, 1H), 6.95 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 6.76 (d, J=8.4 Hz,0.85H), 6.34 (d, J=9.2 Hz, 0.15H), 3.97-3.83 (m, 1H), 2.90-2.65 (m, 4H),1.29 (s, 7.65H), 1.12 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers):δ 155.1, 139.6, 136.1, 129.0, 128.0, 127.5, 125.8, 123.2, 120.8, 118.3,118.1, 111.4, 111.3, 77.3, 52.6, 39.9, 30.4, 28.2 (27.8).

Example 3B: Preparation of tert-butyl(S)-(2-(1H-indol-3-yl)-1-phenylethyl)carbamate

The general reaction as per Example 3A was performed between indole (294mg, 2.51 mmol, 150 mol %) and tert-butyl(S)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg,1.67 mmol, 100 mol %) to yield tert-butyl(S)-(2-(1H-indol-3-yl)-1-phenylethyl)carbamate (398 mg, 71% yield) as awhite solid. The C³/N¹ ratio was 97:3. Column Gradient: 0 to 50% iPrOAcin Heptane. mp: 134.6-135.2° C.; FTIR (neat, cm⁻¹) 3416, 3401, 3371,2980, 2909, 1683, 1524; ¹H NMR (400 MHz, DMSO-d₆) (85:15 mixture ofrotamers): δ 10.74 (br, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.4 Hz,1H), 7.38-7.25 (m, 5H), 7.20 (dd, J=6.8, 7.2 Hz, 1H), 7.06 (dd, J=7.6,7.2 Hz, 1H), 7.02 (s, 1H), 6.98 (dd, J=7.6, 7.2 Hz, 1H), 4.89-4.74 (m,1H), 3.08 (dd, J=14.8, 8.8 Hz, 1H), 2.99 (dd, J=14.4, 6.0 Hz, 1H), 1.31(s, 7.65H), 1.08 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.0, 144.5,136.0, 128.0, 127.3, 126.5, 126.4, 123.2, 120.8, 118.3, 118.2, 111.3,111.3, 77.6, 55.0, 32.8, 28.2.

Example 3C: Preparation of tert-butyl(S)-(2-(1H-indol-3-yl)-1-(4-methoxyphenyl)ethyl)carbamate

The general reaction as per Example 3A was performed between indole (264mg, 2.25 mmol, 150 mol %) and tert-butyl(S)-4-(4-methoxyphenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(495 mg, 1.50 mmol, 100 mol %) to yield tert-butyl(S)-(2-(1H-indol-3-yl)-1-(4-methoxyphenyl)ethyl)carbamate (378 mg, 69%yield) as a white solid. The C³/N¹ ratio was 98:2. Column Gradient: 0 to50% iPrOAc in Heptane. mp: 173.3-176.5° C.; FTIR (neat, cm⁻¹) 3402,3326, 2979, 2925, 2904, 1690, 1611, 1506; ¹H NMR (400 MHz, DMSO-d₆)(85:15 mixture of rotamers): δ 10.72 (br, 1H), 7.54 (d, J=8.0 Hz, 1H),7.39-7.28 (m, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.05 (ddd, J=8.4, 7.2, 1.2Hz, 1H), 7.02-6.94 (m, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.88-4.57 (m, 1H),3.72 (s, 3H), 3.06 (dd, J=14.8, 8.4 Hz, 1H), 2.96 (dd, J=14.8, 6.4 Hz,1H), 1.31 (s, 7.65H), 1.11 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆): δ157.9, 154.9, 136.4, 136.0, 127.5, 127.3, 123.2, 120.7, 118.3, 118.1,113.4, 111.4, 111.2, 77.5, 55.0, 54.4, 32.8, 28.2.

Example 3D: Preparation of tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate

The general reaction as per Example 3A was performed between indole (370mg, 3.16 mmol, 150 mol %) and tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg,2.11 mmol, 100 mol %) to yield tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (406 mg, 70% yield) as awhite solid. The C³/N¹ ratio was 99:1. Column Gradient: 0 to 50% iPrOAcin Heptane. mp: 82.2-84.3° C.; FTIR (neat, cm¹) 3416, 3401, 3366, 2974,2963, 1684, 1524; ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (br, 1H), 7.56 (d,J=7.6 Hz, 1H), 7.33 (ddd, J=8.0, 1.2, 0.8 Hz, 1H), 7.10 (d, J=2.4 Hz,1H), 7.05 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 6.97 (ddd, J=8.0, 6.8, 1.2 Hz,1H), 6.71 (d, J=8.4 Hz, 1H), 3.82-3.66 (m, 1H), 2.87 (dd, J=14.0, 6.0Hz, 1H), 2.65 (dd, J=14.0, 7.6 Hz, 1H), 1.38 (s, 9H), 1.01 (d, J=6.8 Hz,3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.0, 136.1, 127.5, 123.1, 120.7,118.4, 118.1, 111.6, 111.2, 77.3, 46.8, 32.2, 28.3, 20.1.

Example 3E: Preparation of tert-butyl(R)-(1-(1H-indol-3-yl)-3-methylbutan-2-yl)carbamate

The general reaction as per Example 3A was performed between indole (331mg, 2.83 mmol, 150 mol %) and tert-butyl(R)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (500 mg,1.88 mmol, 100 mol %) to yield tert-butyl(R)-(1-(1H-indol-3-yl)-3-methylbutan-2-yl)carbamate (335 mg, 59% yield)as a white solid. The C³/N¹ ratio was 94:6. Column Gradient: 0 to 50%iPrOAc in Heptane. mp: 145.1-146.9° C.; FTIR (neat, cm⁻¹) 3417, 3402,3362, 2978, 1686, 1526; ¹H NMR (400 MHz, DMSO-d₆) (85:15 mixture ofrotamers): δ 10.72 (br, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.31 (ddd, J=8.0,1.2, 0.8 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.04 (ddd, J=8.0, 6.8, 1.2 Hz,1H), 6.96 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 6.59 (d, J=9.2 Hz, 0.85H), 6.15(d, J=10.0 Hz, 0.15H), 3.64-3.53 (m, 1H), 2.80 (dd, J=14.8, 5.2 Hz, 1H),2.68 (dd, J=14.8, 8.8 Hz, 1H), 1.77-1.65 (m, 1H), 1.32 (s, 7.65H), 1.12(s, 1.35H), 0.95-0.82 (m, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 155.6,136.1, 127.5, 122.7, 120.7, 118.3, 118.0, 112.0, 111.2, 77.1, 55.6,31.4, 28.3, 27.1, 19.4, 17.7.

Example 3F: Preparation of tert-butyl(S)-(1-cyclopropyl-2-(1H-indol-3-yl)ethyl)carbamate

The general reaction as per Example 3A was performed between indole (264mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-cyclopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (395mg, 1.50 mmol, 100 mol %) to yield tert-butyl(S)-(1-cyclopropyl-2-(1H-indol-3-yl)ethyl)carbamate (292 mg, 65% yield)as a white solid. The C³/N¹ ratio was 99:1. Column Gradient: 0 to 50%iPrOAc in Heptane. mp: 128.8-130.5° C.; FTIR (neat, cm⁻¹) 3414, 3400,3362, 2981, 2937, 1683, 1525; ¹H NMR (400 MHz, DMSO-d₆) (9:1 mixture ofrotamers): δ 10.73 (br, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.31 (ddd, J=8.0,1.2, 0.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.04 (ddd, J=8.0, 6.8, 1.2 Hz,1H), 6.95 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 6.66 (d, J=8.4 Hz, 0.9H), 6.26(s, 0.1H), 3.30-3.18 (m, 1H), 2.91 (dd, J=14.4, 5.6 Hz, 1H), 2.85 (dd,J=14.4, 8.0 Hz, 1H), 1.33 (s, 8.1H), 1.17 (s, 0.9H), 0.96-0.83 (m, 1H),0.42-0.32 (m, 1H), 0.32-0.24 (m, 2H), 0.15-0.01 (m, 1H); ¹³C NMR (100MHz, DMSO-d₆): δ 155.3, 136.0, 127.7, 122.9, 120.6, 118.4, 118.0, 111.6,111.2, 77.2, 54.2, 30.4, 28.2, 16.0, 3.0, 1.9.

Example 3G: Preparation of tert-butyl((1S,2S)-2-(1H-indol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

The general reaction as per Example 3A was performed between indole (282mg, 2.41 mmol, 150 mol %) and tert-butyl (3aR,8aS)-8,8a-dihydroindeno[1,2-d][1,2,3]oxathiazole-3 (3 aH)-carboxylate2,2-dioxide (500 mg, 1.61 mmol, 100 mol %) to yield tert-butyl((1S,2S)-2-(1H-indol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (304 mg,54% yield) as a white solid. The C³/N¹ ratio was 95:5. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 155.7-157.1° C.; FTIR (neat, cm⁻¹) 3387,3351, 2980, 2938, 1691, 1500; ¹H NMR (400 MHz, DMSO-d₆) (87:13 mixtureof rotamers): 10.85 (br, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.42-7.32 (m, 2H),7.30-7.20 (m, 4H), 7.17 (dd, J=8.0, 4.0 Hz, 1H), 7.07 (ddd, J=8.0, 6.8,1.2 Hz, 1H), 6.97 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 5.18 (dd, J=9.2, 9.2Hz, 1H), 3.69 (dd, J=18.4, 9.6 Hz, 0.87H), 3.64-3.53 (m, 0.13H), 3.37(dd, J=15.2, 8.0 Hz, 0.87H), 3.30-3.23 (m, 0.13H), 3.13-3.04 (m, 0.13H),2.99 (dd, J=15.2, 10.4 Hz, 0.87H), 1.38 (s, 7.83H), 1.12 (s, 1.17H); ¹³CNMR (100 MHz, DMSO-d₆) (rotamers): δ 155.9, 144.5, 141.3, 136.6, 127.2,127.1, 126.4, 124.4, 123.3, 121.7, 120.9, 119.1, 118.2, 115.5, 111.4,77.7, 60.8, 44.0, 37.2, 28.2 (27.7).

Example 3H: Preparation of tert-butyl(S)-(2-(1H-indol-3-yl)propyl)carbamate

The general reaction as per Example 3A was performed between indole (264mg, 2.25 mmol, 150 mol %) and tert-butyl(S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (356 mg,1.50 mmol, 100 mol %) to yield tert-butyl(S)-(2-(1H-indol-3-yl)propyl)carbamate (319 mg, 78% yield) as acolorless liquid. The C³/N¹ ratio was 93:7. Column Gradient: 0 to 50%iPrOAc in Heptane. FTIR (neat, cm¹) 3412, 3327, 2971, 2930, 1685, 1508,1456; ¹H NMR (400 MHz, DMSO-d₆) (9:1 mixture of rotamers): δ 10.78 (br,1H), 7.58 (d, J=7.6 Hz, 1H), 7.33 (ddd, J=8.0, 1.2, 0.8 Hz, 1H), 7.10(d, J=2.0 Hz, 1H), 7.05 (ddd, J=8.0, 6.8, 1.2 Hz, 1H), 6.96 (ddd, J=8.0,6.8, 1.2 Hz, 1H), 6.86 (dd, J=6.0, 6.0 Hz, 0.9H), 6.51 (s, 0.1H), 3.29(ddd, J=13.2, 5.6, 5.6 Hz, 1H), 3.18-3.05 (m, 1H), 2.97 (ddd, J=13.2,8.8, 6.0 Hz, 1H), 1.41 (s, 0.9H), 1.38 (s, 8.1H), 1.25 (d, J=6.8 Hz,3H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers): δ 155.7, 136.4, 126.6,121.0, 120.8, 118.6, 118.1, 117.9, 111.4, 77.4, 46.8, 30.9, 28.3 (28.2),18.4 (18.2).

Example 31: Preparation of tert-butyl(R)-(1-(3-fluorophenyl)-2-(1H-indol-3-yl)ethyl)carbamate

The general reaction as per Example 3A was performed between indole (263mg, 2.25 mmol, 150 mol %) and tert-butyl(S)-4-(3-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(475 mg, 1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-(3-fluorophenyl)-2-(1H-indol-3-yl)ethyl)carbamate (382 mg, 72%yield) as a white solid. The C³/N¹ ratio was 99:1. Column Gradient: 0 to50% iPrOAc in Heptane. mp: 148.6-151.2° C.; FTIR (neat, cm⁻¹) 3414,3398, 3363, 3055, 2981, 1682, 1591, 1527; ¹H NMR (400 MHz, DMSO-d₆) (9:1mixture of rotamers): δ 10.75 (br, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.37-7.26 (m, 2H), 7.20-7.11 (m, 2H), 7.08-6.93 (m, 4H),4.85-4.65 (m, 1H), 3.06 (dd, J=14.4, 8.4 Hz, 1H), 2.98 (dd, J=14.4, 6.4Hz, 1H), 1.30 (s, 8.1H), 1.08 (s, 0.9H); ¹³C NMR (100 MHz, DMSO-d₆): δ162.2 (d, ¹J_(CF)=243 Hz), 155.0, 147.5 (d, ³J_(CF)=7 Hz), 136.0, 129.9(d, ³J_(CF)=8 Hz), 127.2, 123.3, 122.6, 120.8, 118.3, 118.2, 113.3 (d,²J_(CF)=21 Hz), 113.0 (d, ²J_(CF)=21 Hz), 111.3, 111.0, 77.8, 54.7,32.5, 28.2; ¹⁹F NMR (DMSO-d₆, 376 MHz): δ −113.6.

Example 3J: Preparation of tert-butyl(R)-(2-(1H-indol-3-yl)-1-(3-(trifluoromethyl)phenyl)ethyl) carbamate

The general reaction as per Example 3A was performed between indole (176mg, 1.50 mmol, 150 mol %) and tert-butyl(S)-4-(3-(trifluoromethyl)phenyl)-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (368 mg, 1.00 mmol, 100 mol %) to yield tert-butyl(R)-(2-(1H-indol-3-yl)-1-(3-(trifluoromethyl)phenyl)ethyl) carbamate(320 mg, 79% yield) as a white solid. The C³/N¹ ratio was 98:2. ColumnGradient: 0 to 50% iPrOAc in Heptane. mp: 99.3-101.4° C.; FTIR (neat,cm⁻¹) 3414, 3399, 3361, 2982, 2936, 1683, 1523; ¹H NMR (400 MHz,DMSO-d₆) (88:12 mixture of rotamers): δ 10.76 (br, 1H), 7.80-7.45 (m,6H), 7.31 (d, J=8.0 Hz, 1H), 7.08-7.00 (m, 2H), 6.96 (ddd, J=8.0, 7.2,1.2 Hz, 1H), 5.11-4.69 (m, 1H), 3.09 (dd, J=14.4, 8.4 Hz, 1H), 3.00 (dd,J=14.4, 6.4 Hz, 1H), 1.30 (s, 7.9H), 1.07 (s, 1.1H); ¹³C NMR (100 MHz,DMSO-d₆): δ 155.1, 145.8, 136.1, 130.8, 129.0, 128.9 (q, ²J_(CF)=32 Hz),127.3, 124.4 (q, ¹J_(CF)=270 Hz), 123.3 (q, ³J_(CF)=4 Hz), 123.0, 122.8(q, ³J_(CF)=4 Hz), 120.8, 118.3, 118.2, 111.3, 110.8, 77.9, 55.0, 32.5,28.2; ¹⁹F NMR (DMSO-d₆, 376 MHz): δ −61.0.

Example 3K: Preparation of tert-butyl(S)-(3-(1H-indol-3-yl)-1-phenylpropyl)carbamate

The general reaction as per Example 3A was performed between indole (264mg, 2.25 mmol, 150 mol %) and tert-butyl(S)-4-phenyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (470 mg, 1.50mmol, 100 mol %) to yield tert-butyl(S)-(3-(1H-indol-3-yl)-1-phenylpropyl)carbamate (401 mg, 73% yield) as awhite solid. The C³/N¹ ratio was 98:2. Column Gradient: 0 to 50% iPrOAcin Heptane. mp: 121.7-123.2° C.; FTIR (neat, cm⁻¹) 3390, 2979, 2929,2859, 1681, 1507, 1457, 1364; ¹H NMR (400 MHz, CDCl₃) (80:20 mixture ofrotamers): δ 8.04 (br, 0.2H), 7.96 (br, 0.8H), 7.66 (d, J=8.0 Hz, 0.2H),7.52 (d, J=8.0 Hz, 0.8H), 7.40-7.22 (m, 6H), 7.22-7.15 (m, 1H),7.15-7.06 (m, 1H), 7.00 (br, 1H), 4.88 (br, 0.8H), 4.75 (br, 1H), 4.53(br, 0.2H), 3.52-3.35 (m, 0.4H), 3.32-3.20 (m, 0.4H), 2.87-2.67 (m,1.6H), 2.16 (d, J=8.8 Hz, 1.6H), 1.42 (s, 9H); ¹³C NMR (100 MHz,DMSO-d6) (rotamers): δ 155.4 (156.2), 143.0, 136.4 (136.6), 128.6,127.3, 127.2, 126.4, 121.8 (122.0), 121.5 (120.8), 119.0 (119.2), 118.7,115.3, 111.2 (111.3), 79.5, 54.7 (46.7), 37.2 (31.6), 28.4 (29.7), 21.9(18.7).

Example 3L: Preparation of tert-butyl(R)-(1-(5-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

The general reaction as per Example 3A was performed between5-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield of tert-butyl(R)-(1-(5-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (401 mg,73% yield) as a white solid. The C³/N¹ ratio was 92:8. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 123.0-123.8° C.; FTIR (neat, cm⁻¹) 3413,3368, 2974, 2927, 1685, 1524; ¹H NMR (400 MHz, DMSO-d₆) (85:15 mixtureof rotamers): δ 10.63 (br, 1H), 7.30-7.13 (m, 7H), 7.07 (d, J=2.0 Hz,1H), 6.87 (dd, J=8.4, 1.6 Hz, 1H), 6.74 (d, J=8.8 Hz, 0.85H), 6.34 (d,J=7.6 Hz, 0.15H), 3.96-3.80 (m, 1H), 2.86-2.64 (m, 4H), 2.36 (s, 3H),1.30 (s, 7.65H), 1.16 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers):δ 155.1, 139.6, 134.5, 129.1, 128.0, 127.7, 126.4, 125.8, 123.2, 122.3,117.9, 111.0, 110.9, 77.2, 52.7, 40.0, 30.2, 28.2 (27.8), 21.3.

Example 3M: Preparation of tert-butyl(R)-(1-(7-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

The general reaction as per Example 3A was performed between7-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-(7-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (371 mg,68% yield) as a white solid. The C³/N¹ ratio was 97:3. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 124.4-125.9° C.; FTIR (neat, cm¹) 3417,3407, 3370, 2974, 2926, 1683, 1524; ¹H NMR (400 MHz, DMSO-d₆) (85:15mixture of rotamers): δ 10.75 (br d, J=2.0 Hz, 1H), 7.34-7.21 (m, 3H),7.21-7.09 (m, 4H), 6.90-6.83 (m, 2H), 6.74 (d, J=8.8 Hz, 0.85H), 6.34(d, J=7.6 Hz, 0.15H), 3.98-3.84 (m, 1H), 2.91-2.65 (m, 4H), 2.44 (s,3H), 1.31 (s, 7.65H), 1.14 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆)(rotamers): δ 155.2, 139.6, 135.7, 129.0, 128.0, 127.2, 125.8, 122.9,121.3, 120.3, 118.4, 115.9, 111.9, 77.3, 52.6, 39.9, 30.5, 28.2 (27.8),16.7.

Example 3N: Preparation of tert-butyl(R)-(1-(5-chloro-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

The general reaction as per Example 3A was performed between5-chloro-1H-indole (341 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-(5-chloro-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (345 mg,60% yield) as a white solid. The C³/N¹ ratio was 96:4. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 70.5-73.9° C.; FTIR (neat, cm¹) 3417,3368, 2980, 2928, 1684, 1518; ¹H NMR (400 MHz, DMSO-d₆) (85:15 mixtureof rotamers): δ 10.99 (br, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 7.30-7.22 (m, 2H), 7.22-7.13 (m, 4H), 7.04 (dd, J=8.4, 2.0 Hz,1H), 6.77 (d, J=8.8 Hz, 0.85H), 6.34 (d, J=8.8 Hz, 0.15H), 3.90-3.76 (m,1H), 2.83-2.62 (m, 4H), 1.27 (s, 7.65H), 1.10 (s, 1.35H); ¹³C NMR (100MHz, DMSO-d₆) (rotamers): δ 155.1, 139.5, 134.6, 129.0, 128.8, 128.0,125.8, 125.2, 122.9, 120.6, 117.7, 112.8, 111.5, 77.2, 52.9, 40.0, 30.1,28.2 (27.7).

Example 30: Preparation of tert-butyl(R)-(1-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)propan-2-yl)carbamate

The general reaction as per Example 3A was performed between5-(trifluoromethyl)-1H-indole (417 mg, 2.25 mmol, 150 mol %) andtert-butyl (R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(470 mg, 1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)propan-2-yl)carbamate(297 mg, 47% yield) as a white solid. The C³/N¹ ratio was 96:4. ColumnGradient: 0 to 50% iPrOAc in Heptane. mp: 130.9-131.8° C.; FTIR (neat,cm¹) 3417, 3368, 2980, 2929, 1684, 1519; ¹H NMR (400 MHz, DMSO-d₆)(85:15 mixture of rotamers): 11.26 (br, 1H), 7.84 (s, 1H), 7.50 (d,J=8.4 Hz, 1H), 7.37-7.22 (m, 4H), 7.22-7.10 (m, 3H), 6.80 (d, J=8.8 Hz,0.85H), 6.36 (d, J=9.2 Hz, 0.15H), 3.99-3.77 (m, 1H), 2.86 (d, J=6.8 Hz,2H), 2.76 (d, J=6.8 Hz, 2H), 1.22 (s, 7.65H), 1.04 (s, 1.35H); ¹³C NMR(100 MHz, DMSO-d₆) (rotamers): δ 155.1 (154.6), 139.5, 137.6 (137.7),129.1, 128.0, 126.9, 125.8, 125.7 (q, ¹J_(CF)=269 Hz), 125.6, 119.1 (q,²J_(CF)=32 Hz), 117.1 (q, ³J_(CF)=4 Hz), 116.1 (q, ³J_(CF)=4 Hz), 112.9,111.9, 77.2, 53.0 (53.7), 40.3 (41.0), 29.9 (30.9), 28.1 (27.6); ¹⁹F NMR(DMSO-d₆, 376 MHz): δ −58.1.

Example 3P: Preparation of tert-butyl(R)-(1-(5-methoxy-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

The general reaction as per Example 3A was performed between5-methoxy-1H-indole (331 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-(5-methoxy-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (523 mg,92% yield) as a white solid. The C³/N¹ ratio was 97:3. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 123.2-123.9° C.; FTIR (neat, cm¹) 3368,2975, 2933, 1692, 1680, 1516; ¹H NMR (400 MHz, DMSO-d₆) (85:15 mixtureof rotamers): δ 10.60 (s, 1H), 7.32-7.24 (m, 2H), 7.24-7.13 (m, 4H),7.08 (d, J=2.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 0.85H), 6.83 (br, 0.15H),6.77 (d, J=8.8 Hz, 0.85H), 6.70 (dd, J=8.8, 2.4 Hz, 1H), 6.34 (d, J=9.2Hz, 0.15H), 3.94-3.80 (m, 1H), 3.72 (s, 3H), 2.85-2.65 (m, 4H), 1.29 (s,7.65H), 1.13 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers): δ 155.2,152.9, 139.6, 131.3, 129.1, 128.0, 127.8, 125.8, 123.8, 111.9, 111.3,110.8, 100.3, 77.3, 55.3, 52.8, 40.2, 30.2, 28.2 (27.8).

Example 3Q: Preparation of tert-butyl(R)-(1-phenyl-3-(5-phenyl-1H-indol-3-yl)propan-2-yl)carbamate

The general reaction as per Example 3A was performed between5-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-phenyl-3-(5-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (523 mg,82% yield) as a white solid. The C³/N¹ ratio was 97:3. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 68.9-70.8° C.; FTIR (neat, cm¹) 3427,3411, 3392, 3310, 2977, 2929, 1715, 1696, 1506; ¹H NMR (400 MHz,DMSO-d₆) (85:15 mixture of rotamers): δ 10.85 (br, 1H), 7.70 (s, 1H),7.67-7.60 (m, 2H), 7.48-7.33 (m, 4H), 7.32-7.24 (m, 3H), 7.23-7.15 (m,4H), 6.80 (d, J=8.8 Hz, 0.85H), 6.39 (d, J=9.2 Hz, 0.15H), 4.03-3.84 (m,1H), 2.87 (d, J=6.8 Hz, 2H), 2.77 (d, J=6.8 Hz, 2H), 1.24 (s, 7.65H),1.09 (s, 1.35H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers): δ 155.1, 142.0,139.6, 135.8, 130.7, 129.1, 128.6, 128.1, 128.0, 126.6, 126.0, 125.8,124.0, 120.1, 116.6, 112.2, 111.6, 77.2, 53.1, 40.4, 30.1, 28.2 (27.8).

Example 3R: Preparation of tert-butyl(R)-(1-(2-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate

The general reaction as per Example 3A was performed between2-methyl-1H-indole (295 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-(2-methyl-1H-indol-3-yl)-3-phenylpropan-2-yl)carbamate (386 mg,71% yield) as a white solid. The C³/N¹ ratio was 99:1. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 117.6-119.0° C.; FTIR (neat, cm¹) 3440,3385, 2984, 2930, 1684, 1524; ¹H NMR (400 MHz, DMSO-d₆) (83:17 mixtureof rotamers): δ 10.67 (br, 1H), 7.39 (d, J=7.6 Hz, 0.83H), 7.33 (d,J=8.0 Hz, 0.17H), 7.28-7.18 (m, 3H), 7.18-7.07 (m, 3H), 6.96 (ddd,J=8.0, 7.2, 1.2 Hz, 1H), 6.90 (ddd, J=8.0, 8.0, 1.2 Hz, 1H), 6.73 (d,J=8.8 Hz, 0.83H), 6.30 (d, J=8.8 Hz, 0.17H), 3.94-3.74 (m, 1H), 2.85(dd, J=14.0, 6.4 Hz, 1H), 2.75-2.62 (m, 3H), 2.32 (s, 3H), 1.27 (s,7.47H), 1.04 (s, 1.53H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers): 155.1,139.8, 135.2, 132.4, 128.9, 128.7, 128.0, 125.7, 119.8, 118.0, 117.5,110.2, 107.4, 77.2, 53.4, 39.4, 29.9, 28.2 (27.7), 11.4.

Example 3S: Preparation of tert-butyl(R)-(1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-2-yl)carbamate

The general reaction as per Example 3A was performed between2-phenyl-1H-indole (435 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-phenyl-3-(2-phenyl-1H-indol-3-yl)propan-2-yl)carbamate (324 mg,51% yield) as a white solid. The C³/N¹ ratio was 98:2. Column Gradient:0 to 50% iPrOAc in Heptane. mp: 178.5-178.8° C.; FTIR (neat, cm⁻¹) 3380,3354, 3376, 2981, 2932, 1683, 1508; ¹H NMR (400 MHz, DMSO-d₆) (82:18mixture of rotamers): δ 11.14 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.60 (d,J=7.2 Hz, 2H), 7.44 (dd, J=7.2, 7.2 Hz, 2H), 7.35 (dd, J=7.2, 7.2 Hz,2H), 7.21 (dd, J=7.2, 7.2 Hz, 2H), 7.17-6.97 (m, 5H), 6.79 (d, J=9.2 Hz,0.82H), 6.38 (d, J=9.6 Hz, 0.18H), 4.15-3.90 (m, 1H), 3.06 (dd, J=14.0,6.8 Hz, 1H), 2.96 (dd, J=14.4, 7.2 Hz, 1H), 2.64 (d, J=6.8 Hz, 2H), 1.21(s, 7.40H), 0.97 (s, 1.60H); ¹³C NMR (100 MHz, DMSO-d₆) (rotamers): δ155.0, 139.5, 136.0, 134.7, 133.0, 129.2, 128.9, 128.6, 128.0, 127.8,127.1, 125.8, 121.3, 119.2, 118.5, 111.0, 109.2, 77.2, 53.4, 40.2, 28.1(27.6).

Example 3T: Preparation of tert-butyl(R)-(1-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate

The general reaction as per Example 3A was performed between1H-pyrrolo[2,3-c]pyridine (266 mg, 2.25 mmol, 150 mol %) and tert-butyl(R)-4-benzyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (470 mg,1.50 mmol, 100 mol %) to yield tert-butyl(R)-(1-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate (40mg, 8% yield) as a white solid. The C³/N¹ ratio was 98:2. ColumnGradient: 0 to 50% iPrOAc in Heptane. mp: 196.2-197.0° C.; FTIR (neat,cm¹) 3360, 2978, 2931, 1685, 1625, 1524; ¹H NMR (400 MHz, CDCl₃) (90:10mixture of rotamers): δ 8.56 (br, 1H), 8.28 (s, 1H), 7.57 (d, J=6.4 Hz,1H), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 2H), 7.25-7.20 (m, 2H), 6.70 (br,1H), 5.44 (br, 0.10H), 5.24 (d, J=5.6 Hz, 0.90H), 4.52 (dd, J=13.2, 8.4Hz, 1H), 4.36 (dd, J=13.6, 4.8 Hz, 1H), 4.26-4.14 (m, 1H), 3.00 (dd,J=14.0, 7.6 Hz, 1H), 2.91 (dd, J=14.0, 6.8 Hz, 1H), 1.27 (s, 8.10H),1.11 (s, 0.90H).

Example 4 Preparation of azetidinyl-amines

Preparation of compounds of formula (VII) were performed according tothe general scheme below:

R⁵, v, R⁶, and R¹⁰ are as described herein.

Example 4A Preparation of 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate

1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate was preparedaccording to the following reaction scheme:

Tert-butyl azetidin-3-ylcarbamate hydrochloride (109.7 kg, 1.0 eq.) wasdissolved in MTBE (793.4 kg), and 1-bromo-3-fluoropropane (82.3 kg) wasadded. MTBE (14 kg) and water (530 kg) were added followed by LiOH*H₂O(66.0 kg) at 15-25° C. followed by stirring at 50-60° C. After reactioncompletion, an organic phase was separated and then combined1,2-ethanedisulfonic acid dihydrate aqueous solution (247.8 kg) at 0-5°C. The resulting mixture was stirred for 30 min at 15-20° C. An aqueousphase was separated, and 1,2-ethanedisulfonic acid dihydrate (56.85 kg)was added to the organic phase. The resulting mixture was stirred for 5h at 35-40° C. until deprotection was complete. MeOH (884.1 kg) was thenadded at 35-40° C., and the mixture was stirred for 2 h at 35-40° C.After cooling to room temperature, the reaction mixture was stirred for4 h. Solid was collected by filtration and rinsed with aq. MeOH. Thewashed solid was dried at 35-42° C. under reduced pressure to provide106.8 kg of 1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate(63% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 0.7H), 9.63 (s, 0.3H),8.35 (s, 3H), 4.52 (dt, J=47.1, 5.6 Hz, 2H), 4.43-4.08 (m, 5H), 3.36 (s,3H), 2.74 (s, 4H), 2.06-1.77 (m, 2H).

Example 4B Preparation of 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate Via Strain Release Chemistry

Preparation of 2,3-dibromopropan-1-amine hydrobromide (3)

To 1 (20.0 g, 1.0 equiv, 50 wt % in water) was added a solution of K₂CO₃(29.55 g, 1.0 equiv) in water (100 mL) and a solution of Boc₂O (93.32 g,2.0 equiv) in EtOAc (100 mL) at 0° C. The reaction mixture was stirredat 20° C. for 15 h. The organic layer was separated and solvent swappedto EtOH (100 mL) to provide a solution of 2 in EtOH. It was then addedinto a cold (0° C.) solution of Br₂ (71.74 g, 2.1 equiv) in EtOH (60 mL)at 0° C. The reaction mixture was stirred at 20° C. for 16 h, filtered,washed with MTBE (60 mL), dried under vacuum at 40° C. for 15 h toprovide 3 as a colorless solid (43.01 g, 66%): ¹H NMR (400 MHz, CD₃OD) δ4.55-4.47 (m, 1H), 4.01 (dd, J=10.9, 4.6 Hz, 1H), 3.86 (dd, J=10.9, 8.7Hz, 1H), 3.71 (dd, J=13.9, 3.2 Hz, 1H), 3.39-3.33 (m, 1H).

Preparation of N,N-dibenzyleazetidin-3-amine ethane-1,1disulfonate

To a solution of Bn₂NH (33.12 g, 1.0 equiv) in THF (330 mL) was addediPrMgCl*LiCl (1.3 M in THF, 130 mL, 1.0 equiv) at 20° C. and stirred at20° C. for 5 h to provide a solution of Bn₂NMgCl.LiCl in THF. In aseparate reactor was charged 3 (50.0 g, 1.0 equiv) in THF (500 mL),cooled to −60° C. n-BuLi (201 mL, 2.5 M solution in n-hexane, 3.0 equiv)was added into the suspension at −60° C. and stirred at −60° C. for 2 hto provide a solution of 4 in THF. Bn₂NMgCl.LiCl solution was added intothe 4 at −60° C., warmed to 20° C. and stirred at 20° C. for 12 h toprovide a solution of 5 in THF. The reaction mixture was cooled to 0°C., a solution of Boc₂O (73.28 g, 2.0 equiv) in THF (200 mL) was addedat 0° C., stirred at 20° C. for 2 h, cooled to 0° C., quenched with asolution of AcOH (20.16 g, 2.0 equiv) in H₂O (383 mL). The organic layerwas washed 5% Na₂SO₄ (150 mL). The combined aqueous layer was backextracted with MTBE (100 mL×2) to provide a solution of 6. A solution ofethanedisulfonic acid (40.0 g, 1.5 equiv) in MeOH (225 mL) was addedinto the solution at 20° C. and stirred at 40° C. for 20 h. The slurrywas filtered, washed with THF (100 mL), dried under the vacuum (40° C.)for 20 h to provide 7 (69.21 g, 75% yield) as a white solid: ¹H NMR (400MHz, D₂O) δ 7.57-7.44 (m, 10H), 4.66 (t, J=8.2 Hz, 1H), 4.36 (s, 4H),4.10-3.95 (m, 4H), 3.22 (s, 4H). MS ([M+H]⁺) calculated for C₁₇H₂₁N₂253.17, found 253.00.

Preparation of N,N-dibenzyl-1-(3-fluoropropyl)azetidin-3-amine (8)

To a solution of 7 (40.0 g, 1.0 equiv) in MTBE (200 mL) and H₂O (200 mL)was added 1-bromo-3-fluoropropane (17.20 g, 1.5 equiv) and LiOH*H₂O(15.18 g, 4.0 equiv). The reaction mixture was heated to 55° C. andstirred at 55° C. for 20 h, cooled to 20° C. The organic layer wasseparated and washed with 5% Na₂SO₄ (120 mL×2). 8 can be obtained byconcentration of MTBE solution under reduced vacuum as a white solid(22.3 g, 83% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 7.35-7.22 (m, 10H),4.45 (t, J=6.0 Hz, 1H), 4.33 (t, J=6.0 Hz, 1H), 3.45-3.39 (m, 4H),3.28-3.17 (m, 3H), 2.67-2.56 (m, 2H), 2.35 (t, J=7.0 Hz, 2H), 1.64-1.48(m, 2H). MS ([M+H]⁺) calculated for C₂₀H₂₆FN₂ 313.21, found 313.10.

Preparation of 1-(3-fluoropropyl)azetidin-3-amine ethane-1,2-disulfonate

To a solution of 8 (2.00 g, 1.0 equiv) in MeOH (20.0 mL) was added asolution of ethanedisulfonic acid dihydrate (1.23 g, 1.0 equiv) in H₂O(10.0 mL) at 0° C. The reaction mixture was heated to 30° C., passedthrough charcoal cartridge. Pd/C (0.40 g, 0.20 equiv) was then chargedinto the reaction mixture, stirred at 45° C. with 40 psi H₂, filtered,concentrated to 5 mL, charged with MeOH (20.0 mL), stirred at 20° C. for3 h, filtered, washed with MeOH (2 mL) to provide the title compound(1.36 g, 93% yield) as a white solid: ¹H NMR (400 MHz, D₂O) δ 4.70-4.57(m, 3H), 4.57-4.31 (m, 4H), 3.51 (t, J=7.2 Hz, 2H), 3.24 (s, 4H),2.11-1.97 (m, 2H); ¹⁹F NMR (376 MHz, D₂O) 6-219.59.

Example 5 Preparation of (R)-1-(1H-indol-3-yl)propan-2-amine

To a solution of imidazole (102.8 g, 1.51 mol, 1.5 equiv.) in DCM (1.33L) was added SOCl₂ (179.3 g, 1.51 mol, 1.5 equiv.) dropwise at −5 to 0°C. under N₂ over 30 min. The reaction mixture was stirred for 0.5 h at−5 to 0° C. tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate(Boc-alaninol) (177.7 g, 1.01 mol, 1.0 equiv.) in DCM (1.33 L, 7.5 vol.)was added dropwise at −5 to 0° C. over 1 h. The reaction mixture wasstirred for 0.5 h at −2 to 0° C. followed by addition of triethylamine(204 g, 2.02 mol, 2 equiv.) dropwise at −5 to 0° C. The resultingmixture was stirred for 0.5 h or until N-Boc-alaninol was completelyconsumed as determined by GC analysis. Water was added to the reactionmixture (1.3 L) at 0-20° C. The phases were separated, and the aqueousphase was extracted with DCM (1.3 L). The organic phases were combinedand washed with 10 w % citric acid (1.3 L), aq. NaHCO₃ (1.3 L), andbrine (1 L) successively. The organic phase was cooled to 0-10° C.,followed by addition of water (3.1 L) and RuCl₃.xH₂O (2.66 g), and thenfollowed by addition of Oxone (927.1 g, 1.51 mol, 1.5 equiv.). Thereaction mixture was warmed to 22° C. gradually, and held for 3.5 h oruntil the sulfamidite intermediate was completely consumed as determinedby GC analysis. The phases were separated, and the aqueous phase wasfiltered through a pad of Celite (50 g) followed by rinsing with DCM(1.3 L). The filtrate was extracted with the DCM (1.3 L), and theorganic phases were combined and then washed with sat. Na₂S₂O₃ (1.3 L)and brine (1 L×2). The organic phase was dried with Na₂SO₄ (50 g) andthen filtered rinsing with DCM (200 mL). The combined filtrate andwashes were concentrated under vacuum at 30° C. for 1 h, and thenfurther dried under high vacuum to provide 220 g of tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide with >99 wt% in 91.8% isolated yield (corrected) over 2 steps. ¹H NMR (400 MHz,CDCl₃): δ 4.66 (dd, J=9.2, 6.0 Hz, 1H), 4.41 (qdd, J=6.4, 6.0, 2.8 Hz,1H), 4.19 (dd, J=9.2, 2.8 Hz, 1H), 1.54 (s, 9H), 1.50 (d, J=6.4 Hz, 3H).

Other oxidation reactions were run generally according to the procedureimmediately above where the oxidant, catalyst, and solvent were varied.The results are reported in Table 1 below where “Exp.” refers toexperiment number, “Product” refers to tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide and “SM”refers to Boc-alaninol starting material, “LC A %” refers to areapercent purity by liquid chromatography, and “ND” refers to notdetected. The reaction temperature for experiments 1 and 3-9 was 0-25°C. and the reaction temperature for experiment 2 was 0-40° C. Thereaction time for experiments 1-4 and 7 was 4 hours, the reaction timefor experiments 5 and 6 was 8 hours, and the reaction time forexperiments 8 and 9 was 18 hours.

TABLE 1 Oxidant Catalyst Conditions and Yields Product SM Exp.Oxidant/Catalyst Solvent (LC A %) (LC A %) 6B mCPBA (1.3 eq) DCM (10vol) 3.2 94.4 6C Oxone (1.5 eq) MeCN/H₂O 4.1 46.6 (1/1, 10 vol) 6D NaClO(5.26 eq)/NiCl₂ DCM/H₂O 0.5 94.6 (2.6 mol %) (1/1, 10 vol) 6E H₂O₂ (1.3eq)/FeCl₃ H₂O (10 vol) ND 93.2 (5 mol %) 6F NaClO (5.26 eq)/FeCl₂(2.6DCM/H₂O ND >95 mol %) (1/1, 10 vol) 6G NaClO DCM/H₂O ND >95 (5.26eq)/FeCl₃(2.6 mol %) (1/1, 10 vol) 6H NaClO DCM/H₂O 83.1 ND (5.26eq)/RuCl₃(1.3 wt %) (1/1, 10 vol) 6I Oxone DCM/H₂O 83.8 ND (2.0eq)/RuCl₃(1.3 wt %) (1/1, 10 vol) 6J Oxone MeCN/H₂O 70.7 ND (2.0eq)/RuCl₃(1.3 wt %) (1/1, 10 vol)

To a mixture of indole (7.4 g, 63.2 mmol, 1.5 equiv.) and CuCl (5.4 g,54.7 mmol, 1.3 equiv.) in DCM (60 ml) was added MeMgCl (3.0 M in THF,18.7 mL, 56 mmol, 1.33 equiv.) at −15° C. under N₂ over 10 min. Theresulting light yellow mixture was stirred at −20° C. for 10 min, andthen a solution of tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10.0 g,42.1 mmol, 1.0 equiv.) in DCM (40 ml) was added dropwise at −10° C.under N₂ over 30 min. The mixture was stirred at −10° C. for 2 hours oruntil the reaction was complete as judged by TLC (PE/EA=5/1,disappearance of tert-butyl(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide) or by GC.The reaction was quenched by adding 10% citric acid (100 mL) whilemaintaining the internal temperature <5° C. The phases were separated,and the aqueous phase was extracted with DCM (100 mL×2). The organicphases were combined and washed with brine (100 mL×2), followed byaddition to the organic phase of activated carbon (5 g) and Na₂SO₄ (10g). The resulting mixture was stirred at room temperature for 30 minthen filtered. The cake was washed with DCM (50 mL×2). The filtrate andwash were combined and concentrated under vacuum at 30° C. to providecrude tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (16.9 g,40.9 LCA %). Heptane (200 ml) was added to the crude tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate, and the mixture was stirredat room temperature for 1 hour, during which time, off-white solidprecipitated gradually. The solid was collected by filtration, and thecake was washed with heptane (17 mL×3). The solid was dried under highvacuum at 25° C. to provide 7.0 g of tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (25.5 mmol, 97 A %, 99 wt%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 7.55 (d, J=7.9 Hz, 1H),7.32 (dt, J=8.1, 1.0 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 7.05 (ddd, J=8.2,7.0, 1.2 Hz, 1H), 6.96 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 6.71 (d, J=8.0 Hz,1H), 3.76-3.69 (m, 1H), 2.86 (dd, J=13.9, 5.8 Hz, 1H), 2.64 (dd, J=14.1,7.7 Hz, 1H), 1.37 (s, 9H), 1.00 (d, J=6.6 Hz, 3H).

Other indole alkylation reactions were run generally according to theprocedure immediately above where the copper catalyst species and thestoichiometry of the Grignard reagent were varied. The results arereported in Table 2 below where “Exp.” refers to experiment number,“CuX” refers to the copper catalyst species, “eq.” refers toequivalents, “Prod” refers to tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate, “Ni” refers to a by-productwherein the indole amine is alkylated, “BA” refers to a bisalkylbyproduct, and “AY” refers to LC Assay yield, “A %” refers to areapercent purity by liquid chromatography, and “ND” refers to notdetected.

TABLE 2 Indole Alkylation Reaction Conditions and Yields MgMeCl IndoleProd N1 BA AY Entry CuX (eq.) (eq.) (A %) (A %) (A %) (%) 6K CuCl 1.11.2 82.9 1.2 6.5 72.2 6L CuCl 2.2 2.4 87.4 3.0 2.8 84.7 6M Cul 1.1 1.266.4 2.3 1.4 27.7 6N Cul 2.2 2.4 52.1 6.7 nil 12.8 6O CuTC 1.1 1.2 68.00.8 0.9 34.8 6P CuTC 2.2 2.4 59.3 16.2 0.4 28.1 6Q CuCN 1.1 1.2 70.216.7 1.6 22.3 6R CuCN 2.2 2.4 58.9 31.3 1.1 46.8 6S CuSCN 1.1 1.2 57.430.1 1.8 40.9 6T CuSCN 2.2 2.4 61.9 29.4 1.0 54.3

Other indole alkylation reactions were run generally according to theprocedure immediately above where the reaction temperature was varied.The results are reported in Table 3 below where “Exp.” refers toexperiment number, “G temp” refers to the Grignard reagent additiontemperature in ° C., “S temp” refers to the sulfamidate additiontemperature in ° C., “Prod” refers to tert-butyl(R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate, “Ni” refers to a by-productwherein the indole amine is alkylated, “BA” refers to a bisalkylbyproduct, and “AY” refers to LC assay yield, and “A %” refers to areapercent purity by liquid chromatography.

TABLE 3 Variable temperature indole alkylation experiments G Temp S tempProd N1 BA AY Exp (° C.) (° C.) (A %) (A %) (A %) (%) 6U 15~20 −10~−1583.4 1.2 5.7 65.5 6V −5~0   87.6 1.6 6.0 72.1 6W −10~−15 85.8 1.1 6.380.4 6X −20~−25 89.0 1.3 6.4 80.3 6Y −30~−35 79.9 1.8 7.0 80.2 6Z−40~−45 82.8 3.2 6.6 78.9 6AA −10~−15 15~20 85.4 2.5 3.9 75.7 6AB  5~1089.4 2.0 5.7 81.7 6AC   ~0 86.9 1.5 6.9 80.8 6AD −10~−15 85.8 1.1 6.380.4 6AE −20~−25 85.8 0.9 5.5 73.7 6AF −30~−35 88.4 0.8 5.1 70.6

To a solution of tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate(0.5 g, 1.8 mmol, 92 A %) in MeOH (5 mL, 10 vol.) was added HCl in MeOH(10 M, 1.8 mL, 18 mmol) dropwise at 0° C. under N₂ atmosphere over aperiod of 10 min. The resulting solution was stirred at 0° C. for 2 hrs,then at 25-30° C. for 1 h. The solution was concentrated under vacuum at30° C., diluted with water (10 mL), and extracted with DCM (10 mL×2).The pH of the aqueous phase was adjusted to ˜13 with 1 M aq. NaOH at0-10° C. and then extracted with DCM (20 mL×4). The organic phase wasdried over Na₂SO₄ (10 g). The desiccant was filtered, and the cake waswashed with DCM (10 mL). The combined filtrate and wash was concentratedunder vacuum at 30° C. to afford 0.31 g of crude(R)-1-(1H-indol-3-yl)propan-2-amine with 95.8 LCA % and 99.2% ee purityin 97% isolated yield. ¹H NMR: 400 MHz (CDCl₃): δ 1.20 (d, J=: 6, 3H),1.56 (s, br, 2H), 2.69 (dd, J=14, 8, 1H), 2.91 (dd, J=14, 4, 1H),3.30-3.33 (m, 1H), 7.05 (s, 1H), 7.14 (t, J=7, 1H), 7.22 (t, J=7, 1H),7.38 (d, J=8, 1H), 7.64 (d, J=8, 1H), 8.27 (s, 1H).

Example 6 Preparation of(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol

To a solution of 2,2-difluoropropane-1,3-diol (51 kg, 90 wt %, 409.5mol, 1 eq.) in DCM (332 kg, 5 vol.) was added thionyl chloride (58.4 kg,491.4 mol, 1.2 eq.) at 20-25° C. over 2 h. The reaction mixture washeated to 30-35° C., stirred for 2 h, and ice water (255 kg) was addedto quench the reaction. The phases were separated, and the aqueous phasewas extracted with DCM. The organic phases were combined and washed withwater. To the crude organic phase was added water (255 kg) and FeCl₃(1.6 kg), and the biphasic mixture was cooled to −3° C. Bleach [NaClO(8.1 wt %), 680 kg, 1556 mol, 3.8 equiv.] was then added dropwise duringa period of 5 h at −5 to 1° C., and the reaction mixture was stirred for1 h at 0° C. The reaction mixture was filtered through Celite. Thephases were separated, and the aqueous phase was extracted with DCM. Theorganic phases were combined and washed with aq. solution of Na₂SO₃ andbrine, then dried over Na₂SO₄. The desiccant was filtered off, and thefiltrate was concentrated to ca. 100 L. Heptane (80 kg) was added to theresulting suspension, and the mixture was further concentrated to ca.100 L. Solids were collected by filtration and dried under vacuum toafford 52.01 kg of 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide as anoff-white crystal with (72% yield, two steps from2,2-difluoropropane-1,3-diol). ¹H NMR (400 MHz, DMSO-d₆) δ 5.14 (t,J=10.8 Hz, 1H).

Various other catalysts were evaluated for the preparation of5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide generally according to theprocedure immediately above. The results are reported in Table 4 belowwhere “Exp.” refers to experiment number, “diol” refers to2,2-difluoropropane-1,3-diol, “Prod” refers to 90 wt. %5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide and “Yield” refers to assayyield. Each reaction was quenched with 5 volumes of water.

TABLE 4 Conditions for preparation of 5,5-difluoro-1,3,2-dioxathiane2,2-dioxide Exp. Diol NaClO (eq.) Catalyst (mol %) Prod (Yield) 7B  50 g5.26 NiCl₂ (2.8) 78.6% 7C  50 g 5.26 RuCl₃ (2.8) 67.1% 7D  10 g 5.26RuCl₃ (2.0) 57.1% 7E  10 g 5.26 RuCl₃ (2.8) 64.3% 7F  10 g 5.26 CoCl₂(2.8) 65.7% 7G  10 g 5.26 FeCl₃ (2.8) 71.4% 7H  10 g 5.26 FeCl₂ (2.8)75.7% 7I  10 g 5.26 MnCl₂ (2.8) 60.7% 7J 100 g 5.26 NiCl₂ (2.8) 78.3% 7K100 g 5.26 FeCl₃ (2.8) 79.5% 7L 500 g 5.26 FeCl₃ (2.8)   76% 7M  50 g5.26 NiCl₂ (2.8)   78% 7N  32 g 5.26 FeCl₃ (2.8)   76% 7O  32 g 5.26None   63%

In a 2 L flask were placed (R)-1-(1H-indol-3-yl)propan-2-amine (99 wt %,100 g, 568.2 mmol, 1 equiv.), 5,5-difluoro-1,3,2-dioxathiane 2,2-dioxide(97.9 wt %, 108 g, 608 mmol, 1.07 equiv.), K₂CO₃ (55 g, 398 mmol, 0.7equiv.), and acetonitrile (1 L, 10 vol.). The resulting mixture washeated to 80° C. and stirred for 4 hrs. The reaction was cooled to 35°C. and filtered. The cake was washed with acetonitrile (100 mL×2), andp-TsOH monohydrate (119 g, 625.6 mmol, 1.1 equiv.) and water (100 mL, 1vol) were added to the combined filtrate. The resulting biphasic mixturewas heated to 80° C. and stirred for 3 hrs. The mixture was then pouredinto 1 L of ice-water, and the pH of the mixture was adjusted to 9 withsaturated Na₂CO₃ (350 mL) at <5° C. The phases were separated, and theaqueous was extracted with i-PrOAc (500 mL×2). The organic phases werecombined and washed with water (500 mL) and brine (500 mL×2), then driedover Na₂SO₄ (30 g). The desiccant was filtered off, and the cake waswashed with i-PrOAc (100 mL×2). The filtrate and wash were combinedconcentrated under vacuum at 40° C. The residue was dissolved in i-PrOAc(200 mL) and heated to 60° C. Heptane (800 mL) was added dropwise at 60°C., and then the resulting mixture was stirred for 10 min. The mixturewas cooled to 30-35° C. slowly over 2 hrs, and then further cooled to 0°C. After stirring for 10 min, solids were collected by filtration, andthe cake was washed with heptane (100 mL×2). The solid thus obtained wasdried under vacuum at 45° C. to afford(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (155g, 99.2 LCA %, 96 wt %, 97.6% isolated yield). ¹H NMR (400 MHz, DMSO-d₆)δ 10.79 (s, 1H), 7.51 (dd, J=7.9, 1.2 Hz, 1H), 7.33 (dt, J=8.2, 1.0 Hz,1H), 7.13 (d, J=2.3 Hz, 1H), 7.05 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.96(ddd, J=8.0, 6.9, 1.2 Hz, 1H), 5.35 (t, J=6.3 Hz, 1H), 3.61 (td, J=13.8,5.2 Hz, 2H), 3.03-2.91 (m, 3H), 2.83 (dd, J=14.0, 5.7 Hz, 1H), 2.59 (dd,J=14.0, 7.2 Hz, 1H), 1.69 (s, 1H), 0.96 (d, J=6.2 Hz, 3H).

Example 7 Preparation of3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(2R,3R)-2,3-dihydroxysuccinate

In step 1, to a flask with stirring apparatus was combined4-bromo-2,6-difluorobenzaldehyde (131.79 g, 596.35 mmol),(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol (160g, 596.35 mmol), acetic acid (51.26 mL, 894.52 mmol), and toluene. Thereaction was heated to 75° C. and held overnight, cooled, and thendiluted with toluene. The resulting solution was then quenched with anaqueous potassium carbonate solution, washed with brine and water, andtreated with activated charcoal. Following filtration, the solution wasconcentrated and crystallized from toluene/heptane to afford3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-olin 81% yield as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59(s, 1H), 7.45-7.36 (m, 3H), 7.20 (d, J=8.1 Hz, 1H), 7.05-6.92 (m, 2H),5.29 (t, J=6.1 Hz, 1H), 5.21 (s, 1H), 3.71-3.55 (m, 1H), 3.53-3.38 (m,2H), 3.17 (q, J=15.2 Hz, 1H), 2.89 (ddd, J=15.3, 4.8, 1.5 Hz, 1H),2.71-2.55 (m, 2H), 1.08 (d, J=6.5 Hz, 3H). MS ([M+H]+) calculated forC₂₁H₁₉BrF₄N₂O 470.06, found 470.80.

Alternatively, 4-bromo-2,6-difluorobenzaldehyde (67.2 g, 304 mmol),(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1l-ol(80.0 g, 298 mmol), acetic acid (25.6 mL, 447 mmol), and methanol werecombined in a stirred flask. The mixture was refluxed for 24 hours thencooled. Solids were precipitated from the resulting solution by additionof an aqueous solution of potassium carbonate. The resulting slurry wasfiltered and washed to afford3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-olin 97% yield as a pale yellow solid.

In steps 2 and 3,3-((1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(100 g, 212.2 mmol), 1-(3-fluoropropyl)azetidin-3-amineethane-1,2-disulfonate (82.09 g, 254.6 mmol), acetonitrile, DBU (1061mmol 161.5 g 159.4 mL) were combined in a stirred flask followed byaddition of Pd-175 (5.304 mmol 4.144 g). The reaction was heated to 75°C. for 2 hours, cooled, concentrated, and then diluted with methyltert-butyl ether. This resulting solution was worked up with an aqueoussolution of ammonium chloride, brine, and water, then scavenged withSiliaMetS Thiol. Following filtration, the solution was concentrated,diluted with ethanol, and crystallized with tartaric acid to afford3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(2R,3R)-2,3-dihydroxysuccinate in a 90% yield as a yellow solidfollowing filtration and washing. ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s,1H), 7.38 (dd, J=7.5, 1.3 Hz, 1H), 7.21-7.16 (m, 1H), 7.02-6.90 (m, 2H),6.82 (d, J=6.9 Hz, 1H), 6.18-6.08 (m, 2H), 5.07 (s, 1H), 4.53 (t, J=5.8Hz, 1H), 4.42 (t, J=5.9 Hz, 1H), 4.18 (s, 2H), 4.14-4.05 (m, 1H), 3.93(ddt, J=9.1, 7.0, 3.5 Hz, 2H), 3.74-3.60 (m, 1H), 3.51-3.32 (m, 2H),3.21-3.02 (m, 3H), 2.88-2.73 (m, 3H), 2.70-2.51 (m, 2H), 1.83-1.66 (m,2H), 1.09-1.05 (m, 3H). MS ([M+H]+) calculated for C₂₇H₃₁F₅N₄O 522.24,found 523.00.

Example 8 Preparation of3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(2R,3R)-2,3-dihydroxysuccinate

In steps 1-4, a reactor was charged with4-bromo-2,6-difluorobenzaldehyde (75.0 g, 0.339 mol, 100 mol %),p-toluenesulfonic acid monohydrate (162 mg, 0.000849 mol, 0.250 mol %),and toluene (225 mL). Triethyl orthoformate (55.4 g, 62.1 mL, 0.373 mol,110 mol %) was charged over 15 min at rt, the mixture was stirred at rtfor 1 h, and the mixture was distilled to provide a toluene solution of5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene. Another reactor wascharged with 1-(3-fluoropropyl)azetidin-3-amine2-(trioxidanylthio)ethane-1-sulfonate (131.3 g, 0.407 mol, 120 mol %),and acetonitrile (656 mL). DBU (124.0 g, 122.8 mL, 0.814 mol, 240 mol %)was charged over 15 min at rt, and the mixture was stirred at rt for 2h, distilled with toluene, and filtered to provide a toluene solution of1-(3-fluoropropyl)azetidin-3-amine which was charged, along with NaOtBu(39.14 g, 0.407 mol, 120 mol %), to the toluene solution of5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene. The mixture was sparged,charged with BrettPhos Pd G3 (3.076 g, 0.00309 mol, 1.00 mol %),sparged, heated at 60° C. for 18 h, cooled, quenched with water, andwashed with water twice. Siliamets Thiol (20.0 g) was charged and themixture was heated at 50 C for 2 h, cooled, and filtered to provide atoluene solution ofN-(4-(diethoxymethyl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine.Acetic acid (21.4 mL, 0.373 mol, 110 mol %) and water (300 mL) wereadded and the mixture was held at rt for 2 h. An aqueous phase wasseparated, treated with aqueous NaOH (50 wt %, 21.5 mL, 0.407 mol, 120mol %), and seeded with2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino) benzaldehyde(923 mg, 0.00339 mol, 1.00 mol %). The resulting solids were filtered,washed with water, and dried to provide2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde(77.9 g, 84.3% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.05(dd, J=1.2 Hz, 1H), 6.05-5.97 (m, 2H), 5.03 (d, J=6.4 Hz, 1H), 4.54 (t,J=6.0 Hz, 1H), 4.42 (t, J=6.0 Hz, 1H), 4.14-4.03 (m, 1H), 3.70 (td,J=6.8, 1.6 Hz, 2H), 2.99-2.93 (m, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.83-1.66(m, 2H). MS: calcd for C₁₃H₁₅F₃N₂O [M+H]⁺=273.1, observed=273.0.

In step 5, a reactor was charged with(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol(6.60 kg, 24.60 mol, 100 mol %), 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (6.70 kg, 24.60 mol, 100 mol %),L-tartaric acid (5.54 kg, 36.90 mol, 150 mol %), and ethanol (39.6 L).The reaction mixture was heated at 70° C. for 2 h, seeded with3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(2R,3R)-2,3-dihydroxysuccinate (0.0827 kg, 0.123 mol, 0.5 mol %),agitated at 70° C. for 2 days, quenched with ethanol (26.4 L), cooled,and filtered to collect solid. The solid was washed with ethanol anddried under vacuum to provide3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol(2R,3R)-2,3-dihydroxysuccinate (12.7 kg, 78% yield) as an off whitesolid.

Various acids other than tartaric acid, as well as a comparative examplewith tartaric acid, were evaluated for the step 5 ring closure reactiongenerally according to the procedure immediately above. The results arereported in Table 5 below where “Exp.” refers to experiment number, and“Conv” refers to the conversion to the fused tricyclic ring structure.The tartaric acid salt resulted in substantial increase in the finalyield. Further, the tartaric acid salt minimized presence of byproductoligomers formed during synthesis, resulting in purer product and lessepimerization of the final compound product.

TABLE 5 Acids tested for ring closure for Compound A Exp. Acid Conv.Comments 9B Acetic 95% 20% ring opening by-product 9C Trifluoroacetic20% — 9D Methanesulfonic 43% — 9E Benzoic 17% — 9F Pivalic 77% 12% ringopening by-product 9G Diphenylphosphoric 97% 61% isolated yield and 6%oligomers 9H Triflic 60% — 9I Formic 29% — 9J Tartaric 97% 89% isolatedyield and 0.3% oligomers 9K Fumaric 92% 70% isolated yield and 6%oligomers

Example 9

Recrystallization of Compound B.

To a 250 mL reactor was charged crude Compound B (4.00 g, 5.95 mmol) inMeOH (90.0 mL) and EtOH (10.0 mL) mixture. The slurry was heated to 60°C. and became homogeneous. Compound B seeds (200 mg, 0.297 mmol, 5 mol%) were added into the solution. The slurry was distilled with EtOH,cooled to 25° C. over 1 h, held at 25° C. for 1 h, filtered, dried toprovide Compound B (3.83 g, 91% yield) as an off white solid.

Example 10

Recrystallization of Compound B:

Example 10A: To a 30 L reactor was charged crude Compound B (1.26 kg,1.88 mol, 100 mol %) and MTBE (6.30 L, 5.00 mL/g). A solution of NaOH(154 g, 3.85 mol, 205 mol %) in water (6.30 L, 5.00 mL/g) was added intothe slurry. The reaction mixture was stirred at 20° C. for 30 min. Thetop organic layer was washed with water (2.53 L, 2.00 mL/g) twice,passed through charcoal cartridge, distilled with EtOH to provideCompound B freebase solution in EtOH.

Example 10B: To a 20 L reactor was charged with L-tartaric acid (296 g,1.97 mol, 105 mol %), EtOH (2.52 L, 2.00 mL/g) and heated to 70° C. 20%of Compound B freebase solution was transferred into the 20 L reactor.Compound B seeds (25.2 g, 0.0375 mol, 2 mol %) were added into thesolution. The rest of Compound B freebase solution was transferred intothe 20 L reactor over 1 h, aged at 70° C. for 30 min, cooled to 20° C.over 5 h, aged at 20° C. for a minimum of 2 h, filtered, washed withEtOH (2.52 L, 2.00 mL/g) three times, dried to provide Compound B (1.12kg, 89%) as an off white solid.

Example 11

Compounds provided herein were characterized by mass spectrometry and/orNMR techniques as understood in the art. The compounds of this example,unless otherwise noted, have verified stereochemistry.

Example 12

Enzymatic Transformations:

The screening of transaminases in the kinetic resolution mode of rac.alpa-methyltryptamine revealed enzymes possessing sufficient(R)-enantioselectivity for the asymmetric reductive amination approachand sufficient (S)-enantioselectivity for the kinetic resolutionapproach. Exemplary transaminases are listed in Table 6.

TABLE 6 Enantioselective transaminases (TA): (R)-enantioselective TAs(S)-enantioselectivity TAs TA-P2-A01 (Codexis) TA-P1-F03 [Codexis]ESC-ATA01 (Libragen) TA-P1-G05 [Codexis] TA-P2-A07 (Codexis) ATA47[c-LEcta] ATA117 (Codexis) 3FCR_59F_87F_231G* ESC-ATA03 (Libragen)3FCR_59W_87F_231A* 3FCR_59F_86A_87F_152F_231A_234M_382M* 3HMU_264V*ATA12

Asymmetric reduction applying transaminase TA-P2-A07 was performed inbuffer; iso-propyl amine and organic co-solvents such as DMSO orAcetonitrile on 5 g scale. Compound (XXI) was converted to compound (3)as described herein at a degree above 95% with an enantiomeric excess(EE) above 99% after 1 day.

The reductive amination was also performed in organic solventscontaining small amounts of buffer and iso-propyl amine where thetransaminase TA-P2-A07 was immobilized on the solid support. Compound(XXI) was converted to compound (3) at a conversion degree above 95% andan EE above 99% after 4 weeks. The organic solvent enabled highersubstrates loadings up to 5% [w/w].

Kinetic resolution was performed in the presence of transaminase ATA12in (1) whole cells; (2) cell free lysate or (3) crude lyophilisate inbuffer containing pyruvate and organic cosolvent such as acetonitrile.Enantiomeric excess of >99% was achieved. Conversion to compound (3) wasachieved at a degree equal to or above 50%. The undesired enantiomer wasdepleted by oxidative deamination towards the ketone.

Sequence Identification of select TAs: 3FCR Y59F/Y87F/T231G: amino acid(SEQ ID NO: 1)MLKNDQLDQW DRDNFFHPST HLAQHARGES ANRVIKTASG VFIEDRDGTK LLDAFAGL F C 60VNVGYGRQEI AEAIADQARE LAYYHS F VGH GTEASITLAK MILDRAPKNM SKVYFGLGGS 120DANETNVKLI WYYNNILGRP EKKKIISRWR GYHGSGLVTG SLTGLELFHK KFDLPVEQVI 180HTEAPYYFRR EDLNQTEEQF VAHCVAELEA LIEREGADTI AAFIGEPILG  G GGIVPPPAG 240YWEAIQTVLN KHDILLVADE VVTGFGRLGT MFGSDHYGLE PDIITIAKGL TSAYAPLSGS 300IVSDKVWKVL EQGTDENGPI GHGWTYSAHP IGAAAGVANL KLLDELNLVS NAGEVGAYLN 360ATMAEALSQH ANVGDVRGEG LLCAVEFVKD RDSRTFFDAA DKIGPQISAK LLEQDKIIAR 420AMPQGDILGF APPFCLTRAE ADQVVEGTLR AVKAVLG 4573FCR Y59W/Y87F/T231A: amino acid (SEQ ID NO: 2)MLKNDQLDQW DRDNFFHPST HLAQHARGES ANRVIKTASG VFIEDRDGTK LLDAFAGL W C 60VNVGYGRQEI AEAIADQARE LAYYHS F VGH GTEASITLAK MILDRAPKNM SKVYFGLGGS 120DANETNVKLI WYYNNILGRP EKKKIISRWR GYHGSGLVTG SLTGLELFHK KFDLPVEQVI 180HTEAPYYFRR EDLNQTEEQF VAHCVAELEA LIEREGADTI AAFIGEPILG  A GGIVPPPAG 240YWEAIQTVLN KHDILLVADE VVTGFGRLGT MFGSDHYGLE PDIITIAKGL TSAYAPLSGS 300IVSDKVWKVL EQGTDENGPI GHGWTYSAHP IGAAAGVANL KLLDELNLVS NAGEVGAYLN 360ATMAEALSQH ANVGDVRGEG LLCAVEFVKD RDSRTFFDAA DKIGPQISAK LLEQDKIIAR 420AMPQGDILGF APPFCLTRAE ADQVVEGTLR AVKAVLG 4573FCR Y59F/S86A/Y87F/Y152F/T231A/I234M/L382M: amino acid (SEQ ID NO: 3)MLKNDQLDQW DRDNFFHPST HLAQHARGES ANRVIKTASG VFIEDRDGTK LLDAFAGL F C 60VNVGYGRQEI AEAIADQARE LAYYH AF VGH GTEASITLAK MILDRAPKNM SKVYFGLGGS 120DANETNVKLI WYYNNILGRP EKKKIISRWR G F HGSGLVTG SLTGLELFHK KFDLPVEQVI 180HTEAPYYFRR EDLNQTEEQF VAHCVAELEA LIEREGADTI AAFIGEPILG  A GG M VPPPAG240 YWEAIQTVLN KHDILLVADE VVTGFGRLGT MFGSDHYGLE PDIITIAKGL TSAYAPLSGS300 IVSDKVWKVL EQGTDENGPI GHGWTYSAHP IGAAAGVANL KLLDELNLVS NAGEVGAYLN360 ATMAEALSQH ANVGDVRGEG L M CAVEFVKD RDSRTFFDAA DKIGPQISAK LLEQDKIIAR420 AMPQGDILGF APPFCLTRAE ADQVVEGTLR AVKAVLG 457 3HMU I264V: amino acid(SEQ ID NO: 4)MATITNHMPT AELQALDAAH HLHPFSANNA LGEEGTRVIT RARGVWLNDS ALAQKLAELA 60GLWCVNIGYG RDELAEVAAR QMRELPYYNT FFKITHVPAI ALAQKLAELA PGDLNHVFFA 120GGGSEANDTN IRMVRTYWQN KGQPEKTVII SRKNAYHGST VASSALGGMA GMHAQSGLIP 180DVHHINQPNW WAEGGDMDPE EFGLARAREL EEAILELGEN RVAAFIAEPV QGAGGVIVAP 240DSYWPEIQRT CDKYNILLIA DEV V CGFGRT GNWEGIQTMG IRPHIMTIAK GLSSGYAFIG 300GSIVCDEVAH VIGKDEFNHG YTYSGHPVAA AVALENLRIL EEENILDHVR NVAAPYLKEK 360WEALTDHPLV GEAKIVGMMA SIALTPNKAS RAKFASEPGT IGYICRERCF ANNLIMRHVG 420DRMIISPPLV ITPAEIDEMF VRIRKSLDEA OAEIEKQGLM KSAA 464Bolded and underline residues correspond to mutations to naturalsequence.

Example 13

Freebase, Salt, and Polymorph Characterization of Compound A

ABBREVIATIONS

-   -   MIBK Methyl Isobutyl Ketone    -   ACN Acetonitrile    -   EtOAc Ethyl Acetate    -   EtOH Ethanol    -   MTBE Methyl Tert-butyl Ether    -   IPAc Isopropyl Acetate    -   MeTHF Methyl Tetrahydrofuran    -   CPME Cyclopenyl methyl ether    -   MeOH Methanol    -   THF Tetrahydrofuran    -   IPA Isopropyl Alcohol    -   DMSO Dimethyl Sulfoxide    -   DMC Dimethyl Carbonate    -   MEK Methyl Ethyl Ketone    -   DCM Dichloromethane

Free-Base Polymorph Screening.

96-well plate automated High-throughput Screening (HTS) using the SymyxCM2 system (Freeslate Inc., CA) was conducted to identify potentialpolymorphic forms for Compound A free base. Compound A was dispensed ineach well (8 mg/well) using an automated powder dispensing accessoryfollowing which 800 μl of solvent (neat or mixture) was added and theslurry was stirred for 2 hours at 50° C. Compound A was initiallydispensed in the slurry plate using either ethyl acetate (for tartrate)or MIBK (for fumarate) to maintain the solid form. From this masterplate, the supernatant was filtered and distributed to three separateplates for evaporation, precipitation by anti-solvent addition andcontrolled cooling over 8-10 hrs from 50-20° C. In all cases residualsolvents were either evaporated or siphoned off, and the solid wasexamined using polarized light microscopy and XRPD.

Example 14

Salt Screening. According to approximate solubility data of freebase andlist of desired acids, five solvent systems were used in the screening.Approximately 20 mg of freebase amorphous compound was first dispersedin 0.5 mL of selected solvent in a glass vial and corresponding acid wasthen added with a 1:1 ratio of molar charge. An extra molar ratio of 2:1(acid/freebase) was attempted for HCl, due to the two basic functionalgroups. The mixtures were stirred at RT overnight. Resulted solids wereanalyzed by XRPD. Clear solutions obtained after stirring were stirredat 5° C. for 2 days, then 0.5 mL of H₂O was added into each of clearsolutions in ACN/H₂O (19:1, v/v) while 0.5 mL of n-heptane was addedinto each of the clear solutions in the other solvent systems followedby stirring at 5° C. for around 3 days, and the final clear solutionswere transferred to slow evaporation at RT, in order to identify as manycrystalline hits as possible.

The first round of screening identified the crystalline form hits asprovided in Table 7. Tartrate and fumarate were further scaled up to 50mg-1.5 g scale for further characterization. Testing in differentsolvent systems and conditions allowed for a) in-depth characterizationof the different polymorphic forms obtained as hits in the screening andb) identifying conditions to inhibit and control cis-epimer formation.The epimer content varied from <1%-22% in different free base lots.

TABLE 7 Salt screening and crystalline form hits for Compound A. E A B CD ACN/H₂O Acid/Solvent Acetone IPA EtOAc THF (19:1 v/v) Blank Yellow gelYellow gel Yellow gel Light Yellow gel yellow gel Acetic Acid Yellow gelYellow gel Yellow gel Yellow gel Yellow gel Benzene Sulfonic Yellow oilYellow gel Yellow gel Yellow gel Yellow gel Acid Citric Acid Yellow oilYellow gel Amorphous Yellow gel Yellow gel Ethane sulfonic Yellow oilYellow gel Amorphous Yellow gel Yellow gel acid 1,2-EthanedisulfonicAmorphous Amorphous Amorphous Amorphous Dark blue gel acid Fumaric acidYellow oil Yellow gel Fumarate Fumarate Yellow gel Form A Form A Formicacid Yellow gel Yellow gel Yellow gel Yellow gel Yellow gel Gentisicacid Yellow oil Yellow gel Yellow gel Yellow gel Yellow gel Glutamicacid Glutamic Glutamic Glutamic Glutamic Yellow gel acid acid acid acidHydrochloric acid Yellow oil Yellow gel Yellow gel Yellow gel Yellow gel(1:1) Hydrochloric acid Yellow oil Yellow gel Yellow gel Yellow gelYellow gel (2:1) Methanesulfonic Yellow oil Yellow gel Yellow gel Yellowgel Yellow gel acid Malonic acid Yellow oil Yellow gel Yellow gelMalonate Yellow gel Form A Maleic acid Yellow gel Yellow gel Yellow gelYellow gel Yellow gel Phosphoric acid Yellow oil Yellow gel Yellow gelYellow gel Yellow gel p-Toluene sulfonic Yellow oil Yellow gel Yellowgel Yellow gel Yellow gel acid Succinic acid Yellow oil Yellow gelYellow gel Yellow gel Yellow gel Sulfuric acid Yellow gel AmorphousAmorphous Yellow gel Yellow gel L-Tartaric acid Tartrate Yellow gelTartrate Tartrate Yellow gel Form A Form B Form C

Methods:

Ambient X-Ray Powder Diffractometry (XRPD).

XRPD patterns were collected using the PANalytical Empyrean powder X-raydiffractometer (PANalytical Inc., Lelyweg, Netherlands). The powdersample was packed in a zero-background silicon holder and run inreflection mode (Bragg Brentano configuration). The instrument wasequipped a Cu Kc source with tube voltage and current of 45 kV and 40 mArespectively. Data was collected at ambient temperature from 3.0 to40.0° 2θ using a step size of 0.0263°, with a revolution speed of 8 sec.The incident beam path was equipped with a 0.020 soller slit, a fixed 10anti scatter slit, a fixed incident beam mask of 10 mm, and aprogrammable divergence slit in automatic mode. A beam knife for lineardetectors was used. The diffracted beam was equipped with a 0.020 sollerslit, a programmable anti scatter slit in automatic mode, and a nickelK-13 filter. A PIXcel 1D detector was used in the scanning line detector(1D) mode. Data was analyzed using commercial software (JADE®, version9, Materials Data Inc., Livermore, Calif.).

Water Sorption Analysis.

About 5-6 mg of powder sample was placed in the sample pan of anautomated water sorption analyzer (Q5000SA, TA instruments, New Castle,Del.) at 25° C. and a nitrogen flow rate of 200 mL/min. The sample wasinitially “dried” at 0% RH for a total of 400 minutes (at 60 followed by25° C.), following which it was subjected to progressive increase in RHfrom 0-90%, in increments of 10% with a dwell time of 200 minutes atevery RH. This was followed by a progressive decrease in RH indecrements of 10% back to 0% RH, using the same protocol.

Differential Scanning Calorimetry (DSC).

Approximately 3-8 mg of powder sample was analyzed using a DSC Q2000™(TA instruments, New Castle, Del.) equipped with a refrigerated coolingaccessory. Samples were packed in non-hermetically pans (Tzero™,aluminum pans) and typically heated from 0-200° C. at 10° C./min underdry nitrogen purge. The instrument was calibrated using sapphire(baseline) and indium (temperature and cell constant). The data wasanalyzed using commercial software (Universal Analysis 2000, version4.7A, TA Instruments).

Thermogravimetry (TGA).

In a thermogravimetric analyzer (Discovery TGA, TA instruments), 3-5 mgof Compound A samples were heated in an open aluminum pan from RT to350° C. at a heating rate of 10° C./min under dry nitrogen purge.Temperature calibration was performed using Alumel® and Nickel. Standardweights of 100 mg and 1 gm were used for weight calibration.

Polarized Light Microscopy (PLM).

Samples were dispersed in silicon oil and observed under crosspolarizers of a video enhanced Leica DM 4000B microscope equipped with ahigh resolution CCD camera and motorized stage (Clemex TechnologiesInc., Longueuil, Quebec, Canada) at 200× magnification. Photomicrographswere acquired using the Clemex Vision PE software (Clemex TechnologiesInc., Longueuil, Quebec, Canada).

Scanning Electron Microscopy (SEM).

Powder sample sputter coated on SEM stub and then examined using abenchtop Phenom SEM (Nanoscience Instruments, Inc., AZ). Micrographswere acquired at different magnifications.

Particle Size Distribution (PSD).

Particle size analysis was performed using a Malvem Mastersizer 2000instrument equipped with a Hydros 2000SM wet dispersion attachment(Malvem Instruments Ltd., Malvem, UK). ˜40 mg of API was weighed into avial and 1 mL of 0.1% Span 85 in heptane was added. The vial wassonicated for 10 seconds, about 0.5 mL was added to the sampler at astir speed of 1500 rpm, and a PSD was performed at an obscuration of10-20%. Owing to presence of large clusters in the sample that weresettling rapidly out of the suspension, the dispersant was changed to0.2% Span 85 in heptane to stabilize the suspension. External sonicationof 2 followed by two 5 minute duration was applied to break the clustersand PLM images were acquired before and after sonication. The aliquotwas mixed in the sampler for 2 minutes prior to data collection toensure homogeneity. The instrument was rinsed twice with isopropylalcohol (IPA) and once with heptane before being filled with 0.1% Span85 in heptane for each sample. After the last sample had run, theinstrument was rinsed with IPA once. Data for replicates with 5 minutesonication has been reported.

BET Surface Area Analysis.

Surface area measurement was conducted using a Micromeritics ASAP 2460with a Micromeritics Smart VacPrep attachment (Micromeritics InstrumentCorp., GA). A sample of 500 mg-1 g was weighed into an empty ASAP 2460tube and placed on the Smart VacPrep, degassed for 24 hours underambient conditions and then exposed to Krypton gas adsorption at 25° C.and 100 mm Hg hold pressure. An 11 point measurement was made in therelative pressure range of 0.050-0.300 and the data was analyzed usingMicroActive software provided by the vendor.

Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR).

All ¹³C (@ 8 kHz spinning speed) SSNMR experiments were conducted usingthe 500 Mhz Bruker instrument (Bruker BioSpin GmbH, Karlsruhe,Germany)¹³C data were acquired using a CP/TOSS sequence. 1-2 K scanswere collected for signal averaging. A contact time of 2-ms and arecycle delay of 5 seconds was used. Spinal 64 sequence was used fordecoupling with a pulse length of 5.3 microseconds. ¹H 90 degree pulselength of 2.9 microseconds was employed. All ¹⁹F (@ 14 kHz spinningspeed) SSNMR experiments were conducted using the 500 Mhz Brukerinstrument. ¹⁹F data were acquired using a CP and direct polarizationsequences. 64-256 K scans were collected for signal averaging. A contacttime of 750 microseconds and a recycle delay of 7 seconds was used. ¹H90 degree pulse length of 3.54 microseconds was employed.

Example 15

Preliminary characterization of Compound A free base. Compound A freebase was found to be amorphous. The starting material free base CompoundA was characterized by XRPD, TGA and mDSC before screening.). As shownby the characterization results in FIG. 33 and FIG. 34, Compound Astarting material was amorphous with a weight loss of 9.3% up to 220° C.in TGA and no substantial glass transition signal in mDSC. White solidsof freebase Compound A were obtained by anti-solvent addition inMeOH/H₂O (3:20, v/v) with shaking and air dried for ˜7 days.

Polymorph Screening. The solubility of freebase Compound A was estimatedin 16 solvents at RT. (Table 8). Polymorph screening experiments wereperformed using different solution crystallization or solid phasetransition methods. The methods uses and crystal forms identified aresummarized in Table 9.

TABLE 8 Approximate solubility of freebase Compound A Solubility Solvent(mg/mL) Acetone S > 60.0 2-propanol S > 60.0 EtOAc S > 60.0 ACN S > 60.0H₂O S < 1.9* 1,4-Dioxane S > 60.0 EtOH S > 60.0 Toluene S > 60.0 MIBKS > 60.0 MTBE S > 60.0 IPAc S > 60.0 MeTHF S > 60.0 CPME S > 44.0*n-Heptane S < 2.1* Cyclohexanes S < 1.9* Iso-butanol S > 40.0*

TABLE 9 Summary of polymorph screening of freebase Compound A Method No.of Experiments Final Result Solid Vapor Diffusion 13 Amorphous Slurry atRT 25 Amorphous Anti-solvent Addition 15 Amorphous Liquid VaporDiffusion 14 Amorphous Slow Evaporation 12 Gel Total 79 Amorphous

Solid Vapor Diffusion.

Solid vapor diffusion experiments were conducted using 13 differentkinds of solvent. For each experiment, about 15 mg of starting materialwas weighed into a 3-mL vial, which was placed into a 20-mL vial with 2mL of corresponding volatile solvent. The 20-mL vial was sealed with acap and kept at RT for 11 days to allow the solvent vapor to interactwith the solid sample. The isolated solids were tested by XRPD. Assummarized in Table 10, only oil or amorphous was obtained.

TABLE 10 Summary of solid vapor diffusion experiments Solvent FinalResults H₂O Amorphous DCM N/A EtOH Oil MeOH Oil ACN Oil THF N/A CHCl₃Oil Acetone N/A DMF Oil EtOAc N/A 1,4-Dioxane N/A IPA Oil DMSO Oil

Slurry Conversion at RT.

Slurry conversion experiments were conducted at RT in different solventsystems. About 40 mg of starting material was suspended in 0.3 mL ofsolvent in a 1.5-mL glass vial. After stirring, all the clear solutionswere transferred to 5° C., followed by slow evaporation at RT after 3days. Results summarized in

Table 11 indicated that only amorphous, gel or oil was obtained.

TABLE 11 Summary of slurry conversion experiments for freebase CompoundA Solvent, v:v Final Results MeOH Gel EtOH Gel IPA Gel ACN Gel AcetoneGel THF Gel EtOAc Gel 2-MeTHF Gel DCM Gel CPME Gel Acetic acid Gel DMCGel Triethylamine N/A MIBK Gel MTBE Gel Iso-butanol Gel Acetone/H₂O(1:1) Oil ACN/H₂O (1:1) Oil EtOH/H₂O (1:1) Gel EtOH/n-heptane (1:1) GelXylene N/A* Cumene N/A* Cyclohexane Amorphous** N-heptane Amorphous**H₂O Amorphous** *no slow evaporation was applied **solids werecentrifuged and analyzed by XRPD after stirring at RT for 4 days N/A: nosolid obtained

Anti-Solvent Addition.

A total of 15 anti-solvent addition experiments were carried out. About30 mg of starting material was weighed into a 20-mL glass vial anddissolved in 0.15 mL of corresponding solvent at RT. Anti-solvent wasadded stepwise till the precipitation appeared or the total amount ofanti-solvent reached 12 mL, with the sample being stirred magnetically.The precipitate was isolated for XRPD analysis. If no solid wasobserved, the clear solutions were stirred magnetically at 5° C.overnight and then evaporated at RT. Results in Table 12 showed thatonly amorphous or gel was generated.

TABLE 12 Summary of anti-solvent additions experiments for freebaseCompound A Solvent Anti-solvent (v:v) Final Results MeOH H₂O AmorphousEtOH Amorphous Acetone Gel THF Gel ACN Gel EtOH Cyclohexane Gel AcetoneGel EtOAc Gel THF Gel EtOH n-Heptane Gel Acetone Gel EtOAc Gel THF GelMeOH MeOH/H₂O (1:8) Amorphous EtOH EtOH/H₂O (1:8) Amorphous

Liquid Vapor Diffusion.

Liquid vapor diffusion experiments were conducted under 14 conditions(Table 13). About 30 mg of starting material was weighed into each 3-mLglass vial. The corresponding solvent was added to get a solution. Thevial was sealed into the 20-mL glass vial with 3-mL of correspoindinganti-solvent and kept at RT, allowing about 11 days for the vapor tointeract with solution. The precipitates were isolated for XRPDanalysis. Clear solutions were transferred to evaporation at RT.

TABLE 13 Summary of liquid vapor diffusion experiments for freebaseCompound A Solvent Anti-solvent Final Results n-Butanol Cyclohexane Geln-Heptane Gel Xylene Cyclohexane Amorphous n-Heptane AmorphousCyclohexane Amorphous Cumene n-Heptane Amorphous Cyclohexane Gel MEKn-Heptane Gel Cyclohexane Gel IPAc n-Heptane Gel H₂O Amorphous THFCyclohexane Amorphous n-Heptane Amorphous ACN H₂O Gel

Slow Evaporation.

Slow evaporation experiments were performed under 12 conditions. Foreach experiment, around 20 mg of starting material was weighed into a3-mL glass vial, followed by the addition of corresponding solvent orsolvent mixture to get a clear solution. Subsequently, the vial wascovered with parafilm with 3-4 pinholes, and kept at 4° C. to allow thesolution to evaporate slowly. Only gel was obtained, as summarized inTable 14.

TABLE 14 Summary of slow evaporation experiments for freebase Compound ASolvent (v/v) Final Results Xylene Gel Cumene Gel IPAc Gel MIBK Gel MTBEGel DCM/n-heptane (1:1) Gel THF/n-heptane (1:1) Gel Acetone/H₂O (1:1)Gel IPAc/cyclohexane (1:1) Gel MTBE/cyclolexane (1:1) Gel EtOH/H₂O (1:1)Gel EtOH/n-heptane (1:1) Gel

Table 15 summarizes the forms that were obtained via manual screening asdescribed herein.

TABLE 15 Polymorphic forms of Compound A Form Type Polymorph screening:Compound A free base N/A No crystalline hits identified Salt screening:Compound A free base A-tartrate Acetone solvate B-tartrate AnhydrateC-tartrate THF solvate A-malonate THF solvate A-fumarate AnhydratePolymorph screening: Compound A tartrate D Hydrate E DMSO solvate FAnhydrate G Methanol solvate

Example 16

Characterization of Compound B Form A.

Compound B Form A was prepared at 200-mg scale via solution reactivecrystallization in acetone, as evidenced by XRPD (FIG. 1). As shown inFIG. 2a and FIG. 2b , weight loss of about 7.2% up to 125° C. wasobserved in TGA and DSC result showed one endotherm at 124.3° C. (onsettemperature). ¹H NMR showed that its molar ratio was 0.98(acid/freebase) and 5.6% acetone (a molar ratio of 0.69 to freebase) wasdetected. Heating experiments were conducted to further identify Form A.No form change was observed after Form A was heated to 90° C., but thesample turned to amorphous after being heated to 140° C. A considerableamount of acetone (4.5%) was still observed after heating Form A sampleto 90° C. The Form A sample was composed primarily of fine particles andsome aggregates (FIG. 3). Based on the data collected, Compound B Form Ais an acetone solvate and that the loss of solvent is concomitant withmelting.

TABLE 16 Representative XRPD Peaks for Compound B Form A: 2-Theta (°20)d(Å) 4.643 19.0147 8.263 10.6916 9.286 9.5157 11.183 7.9057 11.4957.6916 11.969 7.3884 12.543 7.0515 13.776 6.4228 14.226 6.2207 14.6196.0545 15.092 5.8656 15.564 5.689 16.013 5.5302 17.354 5.1058 18.5594.777 18.847 4.7046 19.321 4.5903 19.821 4.4757 20.265 4.3785 21.3434.1597 21.631 4.105 21.92 4.0515 22.524 3.9443 22.97 3.8686 23.2853.8171 23.549 3.7748 23.942 3.7138 24.81 3.5858 25.964 3.4289

Preparation of Compound B Form A. About 57.5 mg of tartaric acid wasweighed into a 5-mL glass vial, and 2.0 mL acetone was added to get aclear solution. The clear acid solution was added to 2.0 mL freebasestock solution in acetone (˜100 mg/mL) into the 5-mL vial with a molarratio of 1:1, and stirred at RT. About 1 mg of Compound B Form A seedwas added, and the solution turned cloudy. The sample was stirredovernight before taking XRPD measurements as described herein. The thepattern conformed to Compound B Form A. The suspension was then stirredat RT for another 24 hours and the cake dried at 50° C. for 1.5 hrs.Yield: 170.4 mg, with a yield of ˜65.3%.

Example 17

Characterization of Compound B Form B.

Compound B Form B was prepared at 200-mg scale via solution reactivecrystallization in EtOAc, as evidenced by XRPD (FIG. 4). As shown inFIG. 5a and FIG. 5b , a limited weight loss of about 1.3% up to 140° C.was observed in TGA and DSC result showed a melting endothermic peak at156.7° C. (onset temperature). Stoichiometry was determined to be 1.08(acid/freebase) and 1.4% EtOAc (a molar ratio of 0.11 to freebase) wasdetected by ¹H NMR. Based on the characterization data collected,Compound B Form B is an anhydrate.

The solid-state characterization data indicates that Form B issubstantially crystalline (XRPD), and TGA indicates presence of somesurface solvent of ˜2% by an early onset of weight loss from RT-100° C.)with a melting onset of ˜163° C. The melting onset, following a shallowendotherm (vaporization of residual solvent) is at 163° C. Based on thederivative weight loss curve, a very early onset of weight loss (2.4%w/w) was detected up to 100° C., which may be attributed to surfacesolvent. The total weight loss, including that at the melt is 3.5% w/w.Form B was found to be slightly hygroscopic with a moisture pick up of1.2% w/w at 90% RH, 25° C. as shown by the water sorption-desorptionprofile in FIG. 8. The ¹³C (FIG. 6) and ¹⁹F SSNMR spectra (FIG. 7)further indicated formation of Form B. SEM (FIG. 9 a, 500×magnification) and PLM (FIG. 9 b, 200× magnifications) images ofCompound B show Form B comprises of dense spherical aggregates.

TABLE 17 Representative XRPD Peaks for Compound B Form B: 2-Theta (°20)d(Å) 7.684 11.4966 11.491 7.6942 12.54 7.053 14.245 6.2123 15.303 5.785115.557 5.6912 16.014 5.5301 16.634 5.3252 17.371 5.1009 18.242 4.859319.163 4.6278 19.424 4.5662 19.892 4.4597 20.243 4.3833 21.817 4.070522.524 3.9442 22.996 3.8644 23.253 3.8223 23.573 3.7711 24.676 3.604925.073 3.5487 25.915 3.4353

Preliminary stress stability analysis of Compound B Form B. The XRPDpatterns of Compound A salts (fumarate and tartrate) exposed to 40°C./75% RH for one month under open conditions. The solid form did notchange under these conditions.

Although no correlation was observed between epimer content ranging from0.56-0.72% and the solid-state properties of the different salt forms,the SSNMR, XRPD and DSC data indicate that the possibility of obtaininga mixture of forms existed from fumarate salts and that form control ineither salt required a substantial amount of effort downstream, giventhe variability in structural data and melting points with change incrystallization conditions. The tartrate salt lacked the impuritiesfound in the fumarate salt sample at 0.18% upon exposure to 40° C./75%RH for one month.

Compression analysis of Compound B Form B. FIG. 22, FIG. 23, and FIG. 24demonstrate the effect of compression on Compound B tartrate Form B. 250mg compacts of neat Compound B Form B were analyzed. Both SSNMR and XRPD(FIG. 23 and FIG. 22, respectively) show that the form remains unchangedupon compression. A lowering of the ¹⁹F T₁ relaxation time was observedupon compression which is attributable to generation of disorder, albeitvery minor as evident from ¹⁹F SSNMR spectra of the compressed CompoundB Form B in FIG. 23. ¹⁹F T₁ relaxation values are included in Table 18for as is and compressed Compound B Form B. Compression did not affectthe melting point of Compound B Form B, as seen in the DSC thermgram(FIG. 24). Comparative XRPD collected before and after exposure toaccelerated stability conditions of 30° C./65% RH and 40° C./75% RH forup to 6 months (open) demonstrated that Compound A Form B remainsunchanged upon exposure to these conditions.

TABLE 18 ¹⁹F T₁ relaxation times for Compound B Form B T₁ (s) for peaksat T1 (s) for peaks at Sample −96 to −125 ppm −214 to −230 ppmUncompressed (As-is) 12.5 11 Compressed 10.2 9

XRPD of One-Month Stability Sample.

The XRPD of Compound B Form B exposed to 40° C./75% RH for one monthshows the Compound B Form B remains unchanged under stress stabilityconditions including elevated temperature and moisture.

Preparation of Compound B Form B.

About 58.0 mg of tartaric acid was weighed into a 5-mL glass vial, and2.0 mL EtOAc was added. The acid remained undissolved. About 2.0 mLfreebase stock solution in EtOAc (˜100 mg/mL) was added into the 5-mLvial with a molar ratio of 1:1, and the solution was stirred at RT.About 1 mg of Form B seed was added and the solution remained clear. Thesolution was stirred overnight and sampled by XRPD. The patternconformed to Compound B Form B. The suspension was stirred at 50° C. for2 more days. The suspension was centrifuged and the cake dried at 50° C.for 2 hrs. Yield: 144.5 mg, with a yield of ˜56.1^(%).

Example 18

Preparation of Compound B Form C.

Form C was prepared at 200-mg scale via solution reactivecrystallization in THF, as evidenced by XRPD (FIG. 10). As shown in FIG.11a and FIG. 11b , a weight loss of 6.8% up to 130° C. was observed inTGA and DSC showed one endotherm at 118.1° C. (onset temperature). Thestoichiometric ratio was determined to be 1.02 (acid/freebase) and 9.7%

Preparation of Compound B Form C.

About 56.9 mg of tartaric acid was added into a 3-mL glass vial, andadded 1.0 mL THF to get a clear solution. The clear acid solution wasadded to 2.0 mL freebase stock solution in THF (˜100 mg/mL) with a molarratio of 1:1, and stirred at RT. About 1 mg of Form C seed was added,and the solution turned a little turbid. The suspension was stirredovernight and sampled by XRPD. The pattern conformed to Form C. Thesuspension was stirred at RT for another 24 hours, the cake dried at 50°C. for 1.5 hours. The suspension was centrifuged to collect the solids.Yield: 161.4 mg, with a yield of ˜62.7%.

Example 19

Preparation of Compound B Form D.

Form D samples were obtained via fast evaporation in MeOH/DCM and slurryin H₂O at RT, respectively. The XRPD pattern for Form D is shown in FIG.12. TGA and DSC results of Form D sample are provided in FIG. 13a andFIG. 13b , respectively, and show a weight loss of 3.5% before 150° C.and an endotherm at 73.0° C. before melting/decomposition at 163.9° C.(onset temperature). The form change to Form F was observed after Form Dwas heated to 150° C., cooled to 30° C. under protection of nitrogen,and then exposed to ambient condition. No significant amount of processsolvent MeOH or DCM was detected by ¹H NMR and further determined thestoichiometric ratio of L-tartaric acid to freebase to be 1.0. Form D isa hydrate.

To evaluate the physical stability of Form D under different humidity,DVS data of Form D sample was collected at 25° C. after the sample wasequilibrated at ambient humidity (80% RH). A platform from 20% RH (2.25%water uptake) to 80% RH (2.72% water uptake) was observed duringdesorption in DVS test of Form D, suggesting the dehydration of hydrousForm D occurred when relevant humidity value was less than 20%.Furthermore, as the theoretical water content of a monohydrate is 2.6%.Form D is therefore likely to be a monohydrate.

TABLE 19 Representative XRPD Peaks for Compound B Form D: 2-Theta (°20)d(Å) 7.322 12.0634 10.992 8.0426 11.312 7.8161 12.182 7.2597 13.2346.6847 13.487 6.5601 14.114 6.2697 14.668 6.0342 15.145 5.8453 15.7025.6393 16.036 5.5225 16.217 5.4611 16.542 5.3546 17.249 5.1369 17.6375.0246 18.113 4.8935 18.349 4.8311 19.108 4.641 20.209 4.3905 20.5834.3115 21.163 4.1948 21.472 4.135 21.891 4.0569 22.762 3.9036 23.3343.8091 23.569 3.7717

Example 20

Preparation of Compound B Form E.

Form E was obtained via DMSO-mediated crystallization by adding IPAcinto DMSO solution, and its XRPD is shown in FIG. 14. TGA and DSC curves(FIG. 15a and FIG. 15b , respectively) showed a considerable weight lossof 8.3% before 140° C. and an endotherm at 126.3° C. beforemelting/decomposition at 142.6° C. (onset temperature). The ¹H NMRspectrum indicated a 0.7 equivalent of DMSO (˜9.4 wt %) and nosignificant amount of IPAc were detected. The stoichiometric ratio ofL-tartaric acid to freebase was determined to be 1.0. Form E is a DMSOsolvate.

Example 21

Preparation of Compound B Form F.

Form F was obtained via heating a Form D sample to 150° C., cooling to30° C. under protection of nitrogen, and exposed to ambient conditions.The XRPD pattern of Form F is provided in FIG. 16. DSC analysis (FIG.18) indicated that Form F was crystalline with an endothermic peak at164.2° C. (onset temperature). ¹H NMR determined a stoichiometric ratioof L-tartaric acid to freebase to be 1.0 and no significant solventsignal was detected.

TABLE 20 Representative XRPD Peaks for Compound B Form F: 2-Theta (°20)d(Å) 3.925 22.4935 10.54 8.3864 11.724 7.5419 12.52 7.0646 14.227 6.220515.407 5.7466 15.54 5.6976 15.902 5.5687 16.488 5.3721 16.844 5.259417.294 5.1235 18.267 4.8526 18.473 4.799 19.399 4.572 19.661 4.511720.005 4.4348 20.501 4.3286 20.655 4.2968 21.161 4.1952 21.287 4.170621.951 4.0458 22.972 3.8683 23.498 3.783 23.708 3.7499 23.943 3.713724.31 3.6584 24.679 3.6044 24.997 3.5594

To further characterize Form F, variable temperature XRPD (VT-XRPD) wasconducted on Form D where the temperature increased to 150° C. and backto 30° C. under protection of nitrogen. Under such conditions, Form Fwas observed after dehydration of Form D sample at elevatedtemperatures, indicating Form F was an anhydrate.

To evaluate the physical stability of Form F under different humidity,dynamic vapor sorption (DVS) data of Form F was collected at 25° C.after the sample was equilibrated at ambient humidity (80% RH). A wateruptake of ˜1.9% was observed up to 80% RH, suggesting Form F is slightlyhygroscopic.

Preparation of Compound B Form G.

Form G was obtained by slow evaporation in MeOH at RT. The Form GXRPD isprovided in FIG. 19. TGA and DSC results are provided in FIG. 20a andFIG. 20b , respectively, and demonstrated a weight loss of 3.3% before150° C. and a melting/decomposition peak at 170.4° C. (onsettemperature). The ¹H NMR spectrum showed a 0.49 equivalent of MeOH(equal to ˜3.0 wt %). The stoichiometric ratio of L-tartaric acid tofreebase was determined to be 1.0. Form G is a MeOH solvate.

TABLE 21 Representative XRPD Peaks of Compound B Form G; 2-Theta (°20)d(Å) 7.654 11.5416 11.462 7.7139 12.517 7.0663 15.275 5.796 15.5145.7072 16.007 5.5323 17.349 5.1072 18.217 4.8658 19.114 4.6395 19.2944.5966 19.424 4.5661 19.845 4.4702 20.236 4.3846 21.317 4.1647 21.5774.1152 21.791 4.0752 22.497 3.9489 22.971 3.8685 23.228 3.8263 24.6513.6085 25.046 3.5525 25.888 3.4388

Example 22

Polymorph Screening of L-Tartrate.

The solubility of Compound B Form B material was estimated in 20solvents at RT. (Table 22). Approximately 2 mg solids were added into a3-mL glass vial. Solvents in Table 6-7 were then added into the vialsstepwise until the solids were dissolved or a total volume of 1 mL wasreached. Results of Table 22 were used to guide the solvent selection inpolymorph screening. Polymorph screening experiments were performedusing different solution crystallization or solid phase transitionmethods. The methods utilized and crystal forms identified aresummarized in Table 23.

TABLE 22 Compound B solubilities Solvent Solubility (mg/mL) SolventSolubility (mg/mL) DMSO S > 38.0 Anisole S < 1.9 MeOH 6.7 < S < 20.0MTBE S < 2.1 THF 2.1 < S <7.0 2-MeTHF S < 1.9 Acetone 2.1 < S < 7.01,4-Dioxane S < 2.2 EtOH S < 1.9 CPME S < 2.1 IPA S < 2.1 ACN S < 2.1MEK S < 2.0 n-Heptane S < 2.0 MIBK S < 1.9 Toluene S < 1.9 EtOAc S < 1.9H₂O S < 1.9 IPAc S < 1.9 DCM S < 2.0

TABLE 23 Summary of polymorph screenings Method No. of ExperimentsIsolated Solid Forms Anti-solvent addition 14 Form B, D, E Slurryconversion 34 Form B, D, G Slow evaporation 9 Form G Solid vapordiffusion 11 Form B Liquid vapor 12 Form B, Form B + G, diffusion FormB + D Slow cooling 10 N/A Total 84 Form B, D, E, G, B + G, B + D

Anti-Solvent Addition.

A total of 14 anti-solvent addition experiments were carried out. Foreach experiment, about 15 mg of Compound B Form B was weighed into a20-mL glass vial, followed by the addition of 0.3-1.0 mL correspondingsolvent. The mixture was then magnetically stirred at the speed of 500RPM to get a clear solution at RT. Subsequently, the correspondinganti-solvent was added to the solution to induce precipitation or untilthe total amount of anti-solvent reached 10.0 mL. The clear solutionswere transferred to slurry at 5° C. If no precipitation occurs, thesolution was then transferred to fast evaporation at RT. The solids wereisolated for XRPD analysis. Results summarized in Table 24 showed thatCompound B Forms B, D, and E were obtained.

TABLE 24 Summary of anti-solvent addition experiments SolventAnti-Solvent Final Results MIBK MeOH Form D* EtOAc Form D** DCM Form D**IPA Form D** 1,4-Dioxane Amorphous ACN Amorphous THF Form B* TolueneDMSO Form E MEK N/A IPAc Form E 2-MeTHF N/A CPME Yellow oil H₂O N/A EtOHN/A *solid was obtained via stirring at 5° C. **solid was obtained viafast evaporation at RT N/A: no solid was obtained

Example 24

Slurry Conversion at RT. Slurry conversion experiments were conducted atRT in different solvent systems. For each experiment, about 20 mg ofCompound B Form B was suspended in 0.3 mL corresponding solvent in a1.5-mL glass vial. After the suspension was magnetically stirred for 17days at RT, the remaining solids were isolated for XRPD analysis.Results summarized in Table 25 showed that Compound B Forms B, D, and Gwere obtained.

TABLE 25 Summary of slurry conversion experiments at RT. Solvent (v:v)Final Results MeOH Form G EtOAc Form B Acetone Form B Anisole Form BMTBE Form B CPME Form B 2-MeTHF Form B ACN Form B Toluene Form B DCMForm B H₂O Form D* EtOH Form B IPAc/DMSO, 9:1 Form E MIBK/MeOH, 9:1 FormB EtOH/H₂O, 97:3, a_(w) = 0.2 Form B EtOH/H₂O, 92.7:7.3, a_(w) = 0.4Form B EtOH/H₂O, 86:14, a_(w) = 0.6 Form B EtOH/H₂O, 71:29, a_(w) = 0.8Form D *heating-cooling was performed on the sample after being stirredfor 17 days.

Example 25

Slurry Conversion at Elevated Temperatures. Slurry conversionexperiments were conducted at 50° C. and 70° C. in different solventsystems. For each experiment, about 20 mg of Compound B Form B wassuspended in 0.3 mL corresponding solvent in a 1.5-mL glass vial. Afterthe suspension was magnetically stirred for 17 days at 50° C. and 70°C., the remaining solids were isolated for XRPD analysis. Resultssummarized in Table 26 indicated that Compound B Form B was obtained.

TABLE 26 Summary of slurry conversion experiments at elevatedtemperatures Solvent, v:v Temperature, ° C. Final Results H₂O 50 Form BMeOH Form B Acetone Form B THF Form B MEK Form B EtOAc Form B CHCl₃ FormB ACN Form B EtOH Form B MTBE Form B IPA 70 Form B 1-Butanol Form B MIBKForm B IPA Form B Anisote Form B Toluene Form B

Example 26

Slow Evaporation. Slow evaporation experiments were performed under 9conditions. For each experiment, around 15 mg of Compound B Form B wasweighed into a 3-mL glass vial, followed by the addition ofcorresponding solvent or solvent mixture to get a clear solution.Subsequently, the vial was covered with parafilm with 3-4 pinholes, andkept at RT to allow the solution to evaporate slowly. The isolatedsolids were tested by XRPD. As summarized in

Table 27, Compound B Form G was generated.

TABLE 27 Summary of slow evaporation experiments Solvent (v:v) FinalResults MeOH Form G Acetone Yellow gel EtOH Yellow gel 2-MeTHF Yellowgel THF Yellow gel ACN/MeOH, 1:3 Yellow gel EtOAc/MeOH, 1:3 Form GDCM/MeOH, 1:3 Form G Anisole/MeOH, 1:3 Yellow gel

Example 27

Solid Vapor Diffusion. Solid vapor diffusion experiments were conductedusing 11 solvents. For each experiment, about 15 mg of Compound B Form Bwas weighed into a 3-mL vial, which was placed into a 20-mL vial with 4mL of corresponding solvent. The 20-mL vial was sealed with a cap andkept at RT for 14 days to allow the solvent vapor to interact with thesolid sample. The isolated solids were tested by XRPD. The resultssummarized in Table 28 indicated that Compound B Form B was obtained.

TABLE 28 Summary of solid vapor diffusion experiments. Solvent FinalResults H₂O Form B DCM Form B EtOH Form B MeOH Form B ACN Form B THFForm B CHCl₃ Form B Acetone Form B EtOAc Form B 1,4-Dioxane Form B IPAForm B

Example 28

Liquid Vapor Diffusion. Twelve liquid vapor diffusion experiments wereconducted. For each experiment, about 15 mg of Compound B Form B wasdissolved in 0.5-1.0 mL of corresponding solvent to obtain a clearsolution in a 3-mL vial. Subsequently, the solution was placed into a20-mL vial with 4 mL of corresponding anti-solvent. The 20-mL vial wassealed with a cap and kept at RT, allowing sufficient time for solventvapor to interact with the solution. Solids were isolated for XRPDanalysis. Results summarized in Table 29 showed that Compound B Form Band a mixture of Form B+G/B+D were obtained.

TABLE 29 Summary of liquid vapor diffusion experiments. Anti-solventSolvent Final Results 1,4-Dioxane MeOH Form B MeOH Form B + G AcetoneForm B + G ACN Form B + G THF Form B + D EtOAc Form B + G CHCl₃ DMSO N/AMTBE N/A 2-MeTHF N/A DMC N/A IPAc N/A Anisole N/A N/A: no solid obtained

Example 29

Slow Cooling. Slow cooling experiments were conducted in 10 solventsystems. For each experiment, about 20 mg of Compound B Form B wassuspended in 1.0 mL of corresponding solvent in a 3-mL glass vial at RT.The suspension was transferred to slurry at 50° C. with a magneticstirrer at the speed of 500 RPM. The sample was equilibrated at 50° C.for 2 hrs and filtered using a 0.45 μm Nylon membrane. Subsequently, thefiltrate was slowly cooled down from 50° C. to 5° C. at a rate of 0.1°C./min. The results summarized in

Table 30 indicated that no solid was observed.

TABLE 30 Summary of slow cooling experiments. Solvent, v:v Final ResultsMeOH N/A EtOH N/A Acetone N/A MEK N/A THF N/A 2-MeTHF N/A H₂O N/AACN/DMSO, 4:1 N/A Toluene/MeOH, 3:1 N/A EtOAc/MeOH, 3:1 N/A

Example 30

Phase transformation. Crystallization of Compound B from solvents suchas ethyl acetate, ethanol, acetone or and aqueous mixture of these mayresult in the formation of one more of the following forms: anhydrousForm B, anhydrous Form F, monohydrate Form D, and acetone solvate FormA. The XRPD patterns of these four solid forms are shown in FIG. 21. Itwas therefore important to know the physical stability of these forms todetermine the complete phase transformation landscape and controlcrystallization to obtain the desired Form B. Owing to the closeproximity of melting points of Forms F and B (160-164° C. onset for FormF vs 166-175° C. for Form B), form conversion was slow in competitiveslurry bridging experiments at RT and a mixture of both forms wasobtained. As a result, equilibrium solubility studies were conducted forboth forms in ethanol over 17 hrs at 25, 35 and 50° C. to determinetheir thermodynamic stability relationship.

Form F was found to have higher solubility at these three temperatures,confirming Form B to be the thermodynamically stable form from 25-50° C.The Van′t Hoff plot of solubility of Forms B and F vs temperature showedthat the two anhydrates were related enantiotropically with a transitiontemperature at ˜19° C. In case of hydrate-anhydrate stability, it wasfound that Form B remained stable at water activity (a_(w)) a_(w)<0.2(RT), above which the hydrate Form D was stable. However, Form B wasfound to be kinetically stable up to a_(w) of 0.4 (RT) in slurrybridging experiments for up to 36 days. This suggests that although thecritical a_(w) value for form conversion to hydrate is low, there is alarge kinetic barrier for the conversion of Form B to Form D.

Slurry and crystallization samples. Form B+Form A

1:1 mixtures of Compound B lots comprising (1) mixture of Form A/acetonesolvate and Form B) and (2) Form B were made and added to 100% acetoneand aqueous mixtures of acetone water (90% acetone, 95, 96, 97, 98 and99% acetone v/v). Samples were slurried at RT for 120 hrs, filtered andthen analyzed by XRPD.

Form F

Form F was slurried in 100% ethanol at RT and 50° C. overnight. One ofthe suspensions was seeded at RT with Form B while the other was leftunseeded. The suspension stirred at 50° C. was seeded with Form B.Samples were filtered and analysed by XRPD. Samples of Form F wereslurried separately at RT in 100% DI water, 1:1 acetone/water and 100%acetone. Slurries of Form F in neat solvents were maintained at RTwhereas a solution of Form F was obtained in the 1:1 acetone:watermixture which was thus agitated at 5° C. for coolingcrystallization/precipitation. After 24 hrs, all samples were filteredand analyzed by XRPD. Form F was also slurried in 95:5 acetone:water and97:3 acetone:water mixtures at 50° C. for 2 hrs after which the slurrieswere cooled to RT, filtered and analyzed by XRPD. Finally, Form F wasrecrystallized from 95:5 acetone:water seeded with Form B at 50° C.

Form D

Form D was slurried at RT for 48 hrs in 100% ethanol. The sample wassubsequently filtered and analyzed by XRPD.

Results

Development of calorimetric method to estimate purity. Switching fromethanol to acetone/water as the crystallization solvent saw a markedimprovement in purity, with oligomer content dropping by an average of5% w/w, with acceptable yield. The change in oligomer content as well asyield was a function of slurry solvent composition. An increase in thewater content improved purity but lowered the yield. For a given solventcomposition, the melting point onset and % oligomer content consistentlyshowed opposing results, indicating that purity is likely to affect themelting point, with greater % oligomer depressing the melting point andvice versa. Based on this observation, several slurry lots obtained fromacetone/water were analyzed using DSC and tested for oligomer content bySEC and a correlation curve was developed. XRPD data was collected forall these samples to ensure that they conformed to Compound B Form B.Using the exponential fit to the data, purity estimates were made forseveral lots, including a 20 gm scale up and IPC sample. An R² value of0.96 was obtained for the linear fit between experimental and predictedoligomer content. Given that these were solid/powder samples withinherent issues of sample homogeneity, this high R² value providedconfidence in the robustness of the correlation determined betweenmelting point onset and purity.

Compound B Form B was consistently obtained from 100% ethanol (slurry orcrystallization). Further conditions were conducted including slurry orcrystallizations from ethanol/water and slurry in acetone/water (≥95%acetone). Depending on the slurry and crystallization parameters,several other solid forms of Compound B were obtained, namely Form F(ethanol/water) Form A/acetone solvent (>95% acetone) and mixtures ofForm A and B or Form A and F. In conditions where Form F was obtained,the formation of an intermediate hydrate (Form D) was postulated sincea_(w) values of ethanol/water mixtures employed for these samples werewell above 0.2 (RT), where the hydrate is thermodynamically stable.Table 31 shows the crystallization conditions with the form obtained.Since mixtures of forms were obtained in several cases, a form controlstrategy was implemented to obtain Form B in the final solid phase.

TABLE 31 Crystallization conditions and corresponding solid forms Formidentified Crystallization condition (XRPD) Acetone/water(96:4), 5 vol,50 C. for 6 h Form A + Form B Acetone/water(95:5) Form A + Form BAcetone/water(99:1), 5 vol, 50 C. for 2 h Form A + Form B crystallizeGMP batch: 4 vol acetone/water 90:10, Form A + Form F 8 vol acetoneanti-solvent with 1% Form B seeds Seeded crystallization inethanol/water 65:35 Form F

Since acetone/water system was the most effective in purging oligomersfrom Compound B, a competitive slurry bridging experiment was conductedusing 1:1 mixtures of two separate lots of Compound B: one that waspredominantly Form A with some Form B and a second that was slurried inacetone/water mixtures of various compositions at RT for 120 hrs.Acetone solvate was obtained as the stable form at ≥95% acetone while amixture of Form B and Form D hydrate was obtained at 90% acetone. As thedesired acetone level was between 96 and 95% (to oligomer levels), therewas a possibility of obtaining any of Forms A, B, or D from the finalcrystallization.

Form control strategy: conversion of Forms A and F to Form B. FIG. 2bshows the DSC thermograms of Form A acetone solvate. The first endothermat 124° C. indicates solvent loss and vaporization while the secondendotherm at 164° C. denotes the melting of the corresponding anhydrate.XRPD confirmed this anhydrate to be Form B when Form A was heated to152° C. Form A was re-slurried in 100% ethanol overnight for conversionto Form B. Thus a two-step slurry process was proposed to aid formcontrol for Compound B to obtain Form B in the event that the firstslurry in acetone/water produces either Form A or a mixture for Form Aand B, depending on the slurry conditions. This would ensure thatirrespective of a change in form during the first slurry, Form B wouldbe the final Compound B form that is isolated after the second slurrystep.

Unlike the acetone solvate, Form F obtained from a 65:35 ethanol:watercrystallization seeded with Form B showed only one melting endotherm at162° C. Owing to near identical solubility values of Forms F and B inethanol at 25° C. (0.23 mg/mL for Form B vs 0.26 mg/mL for Form F), thethermodynamic driving force for conversion of metastable Form F tostable Form B is less and thus Form F→Form B conversion rate would beslow, even in the presence of Form B as seeds. Irrespective of seedingand temperature, Form F→Form B conversion is slow and a mixture of bothforms is obtained after 12 hours.

To facilitate Form F→Form B conversion in shorter timescales, a solvateroute was adopted wherein Form F would be converted to Form B viaacetone solvate or hydrate formation, which would subsequently bedesolvated to Form B. Form F was slurried overnight in neat water,acetone and 1:1 acetone:water mixture, without any seeding. Form Fremains unchanged in 100% acetone but converts to hydrate (Form D) inpresence of water. When the hydrate is slurried in neat ethanol, amixture of Form D and Form F results, thus indicating the propensity ofthe hydrate to desolvate to the metastable anhydrous form. Form Fslurried in 95:5 acetone:water and 97:3 acetone:water at 50° C.demonstrated that Form B appears but the conversion is incomplete.Recrystallization of Form F from 95:5 acetone:water using Form B seedsat 50° C. resulted in complete conversion Form F→Form B. FIG. 25 andFIG. 26 provide schematics of form conversion between Forms A, B, D andF.

Thermodynamic Relationship between Anhydrous Form B and Form F by slurrycompetition between anhydrous Form B and F. To determine thethermodynamic stability between Form B and F, competitive slurryexperiments were conducted in solvent systems of acetone/EtOH/EtOAc atRT (25±3° C.) and 50° C. as listed in Table 32. A mixture of Form B andF with equal mass ratio was suspended in saturated acetone/EtOH/EtOAcsolutions of Form B and then magnetically stirred at targetedtemperature. After slurry for about 4-11 days, remaining solids wereisolated for XRPD characterization. A mixture of Form B and F wasobserved, indicating slow transition between Form B and F.

TABLE 32 Slurry competition conditions for thermodynamic relationshipbetween Compound B Form B and Form F. Starting Form Solvent Temperature(° C.) Solid Form Form B + F Acetone 50 Form B + F (sampled after 5days) EtOH RT Form B + F (sampled after 4 days) 50 Form B + F (sampledafter 11 days) EtOAc RT Form B + F (sampled after 8 days)

The thermodynamic stability relationship between anhydrous Form B and Fwas determined via slurry competition and equilibrium solubilitymeasurement. As a result, a mixture of Form B and F was observed in allthe slurry competition experiments, indicating slow transition betweenForm B and F. Without being bound by any particular theory, Form B andForm F low solubility may be caused by their low solubility in testedsolvents (acetone/EtOH/EtOAc). Therefore, equilibrium solubility (17hours) was measured in EtOH at 25° C., 35° C. and 50° C., respectively,to determine their thermodynamic stability relationship. Compared withForm B, Form F showed higher solubility under all the three testedtemperatures in EtOH, indicating Form B is thermodynamically more stablethan Form F from 25° C. to 50° C.

The a_(w) between anhydrous Form B and hydrous Form D was determined viaslurry competition under various water activity conditions at RT. Form Dwas observed in a_(w) of 0.6 and 0.8 after one week and in water after36 days. Form B was observed in EtOH (a_(w)<0.2) after one week. Amixture of Form D and B was observed in a_(w) of 0.2 and 0.4 systemsafter stirring at RT for 36 days. To further confirm the thermodynamicstability relationship between Form B and Form D in a_(w) of 0.2 and 0.4systems at RT, their equilibrium solubility (24 hours) under thecorresponding conditions was collected. Compared with that of samplesthat started with Form B, lower solubility was observed in samples thatstarted with Form D (crystal forms of the final limited solids were notchecked) in both a_(w) of 0.2 and 0.4 systems.

Equilibrium Solubility Measurement of Anhydrous Form B and F. To furtherdetermine the thermodynamic stability between Form B and F, equilibriumsolubility measurement experiments were conducted in EtOH at 25° C., 35°C. and 50° C., respectively. Detailed procedures are summarized asfollows: solids of Form B and F were suspended in 0.4 mL of EtOH attargeted temperatures and magnetically stirred for 17 hrs (750 rpm).After centrifugation, the concentration and HPLC purity of freebase inthe filtrate was tested. The crystal form of remaining solids waschecked by XRPD.

Compared with Form B, Form F showed higher solubility at 25° C., 35° C.and 50° C. in EtOH (Table 33). Based on the XRPD results, no form changewas observed after solubility test, indicating Form B is likelythermodynamically more stable than Form F from 25° C. to 50° C.

TABLE 33 Summary of equilibrium solubility measurements of Form B andForm F in EtOH Starting Form Temperature (° C.) Final Form Solubility(mg/mL)* Form B 25 Form B 0.23 Form F Form F 0.26 Form B 35 Form B 0.30Form F Form F 0.36 Form B 50 Form B 0.49 Form F Form F 0.82

indicates data missing or illegible when filed

Critical Water Activity Determination between Form B and D. To determinecritical water activity between anhydrous Form B and hydrous Form D,slurry competition was performed in various water activity conditions atRT as listed in Table 34. A mixture of Form B and D with equal massratio was suspended in saturated EtOH-water (with various a_(w))solutions of Form B and then magnetically stirred at RT. After slurryfor about 7-36 days, remaining solids were isolated for XRPDcharacterization.

TABLE 34 Summary of slurry competition of Form B and Form D undervarious a_(w) conditions Starting Sample Time Form Solvent (v:v, a_(w))(d) Solid Form Form B + D EtOH 7 Form B EtOH:H₂O (97:3, 0.2) 36 Form D +B EtOH:H₂O (92.7:7.3, 0.4) 36 Form D + B EtOH:H₂O (86:14, 0.6) 7 Form DEtOH:H₂O (71:29, 0.8) 7 Form D H₂O 36 Form D

Form D was observed in a_(w) of 0.6 and 0.8 after slurry for one weekand in water after 36 days. Form B was observed in EtOH after slurry forone week. A mixture of Form D and B was observed in a_(w) of 0.2 and 0.4systems after stirring at RT for 36 days.

Solubility Measurement of Form B and D. To further confirm thethermodynamic stability relationship between Form B and Form D undera_(w) of 0.2 and 0.4 conditions at RT, equilibrium solubility under theconditions set forth in Table 35 was collected.

TABLE 35 Summary for equilibrium solubility measurement of Form B and Din a_(w) = 0.2/0.4 systems Starting Form A_(w), solvent systemSolubility (mg/mL) Form B 0.2, 24.4 Form D EtOH:H₂O 21.7 (97:3, v/v)Form B 0.4, 27.5 Form D EtOH:H₂O 18.6 (92.7:7.3, v/v)

indicates data missing or illegible when filed

Solids of anhydrous Form B and hydrous Form D were suspended in 0.5 mLof target solvent system (a_(w)=0.2/0.4), respectively, and magneticallystirred for 24 hrs (750 rpm). The suspension was filtered and theconcentration of freebase in the filtrate was tested. Lower solubilitywas observed in samples that started with Form D. Hydrous Form D appearsthermodynamically more stable than anhydrous Form B when a_(w)≥0.2 at RT(25±3° C.).

Example 31

Malonate Form M

One malonate hit with low crystallinity, malonate Form M, was obtainedfrom screening. Its XRPD pattern is shown in FIG. 31. A weight loss of4.1% up to 110° C. was observed in TGA and DSC result showed multipleendotherms (FIG. 32). Stoichiometry was determined to be 0.50(acid/freebase) and 6.2% THF (a molar ratio of 0.58 to freebase) wasdetected by ¹H NMR. Since multiple endotherms and considerable amount ofTHF are observed, malonate Form M is a THF solvate, but no furthercharacterization was conducted due to its low crystallinity.

Example 32

Fumarate Form 1

One crystalline fumarate hit, fumarate Form 1, was obtained fromscreening. A weight loss of 0.9% up to 150° C. was observed in TGA andDSC (FIG. 28 depicts the TGA and DSC for Compound C Form 1.

FIG. 29) result showed one melting endothermic peak at 164.3° C. (onsettemperature). Stoichiometry was determined to be 0.88 (acid/freebase)and 1.5% EtOAc (a molar ratio of 0.11 to freebase) was detected by ¹HNMR.

Preparation of Fumarate Form 1. About 44.7 mg of fumaric acid wasweighed into a 5-mL glass vial, and 2.0 mL EtOAc was added. The acidremained undissolved. About 2.0 mL of freebase stock solution in EtOAc(˜100 mg/mL) was added into the 5-mL vial with a molar ratio of 1:1, andstirred at RT. About 3 mg of fumarate Form 1 seed was added, and thesolution turned cloudy. The suspension was stirred overnight and sampledby XRPD (FIG. 27) with a confirmed pattern conformed to fumarate Form 1.The suspension was stirred at 50° C. for 3 more days to increase thecrystallinity followed by centrifugation. The cake was dried at 50° C.for 4 hrs. Yield: 186.6 mg, with a yield of ˜76.2%.

TABLE 36 Representative XRPD Peaks for Compound C Form 1. 2-Theta (°2θ)d (Å) 7.589 11.6401 10.596 8.3423 11.449 7.7224 11.844 7.4662 12.57.0758 14.444 6.1275 15.454 5.729 15.782 5.6107 16.097 5.5017 17.5555.0479 18.921 4.6865 19.696 4.5038 19.866 4.4657 20.233 4.3853 21.354.1585 22.046 4.0288 23.162 3.837 23.897 3.7206 24.238 3.669 24.6723.6055 25.236 3.5261 25.932 3.4331

TABLE 37 Representative XRPD Peaks for Compound C Form 2. 2-Theta (°2θ)d (Å) 11.521 7.6744 11.879 7.4439 15.558 5.691 16.04 5.5211 16.5155.3633 17.324 5.1146 18.361 4.8281 19.004 4.6662 19.439 4.5628 19.8764.4634 20.244 4.383 21.355 4.1574 22.035 4.0306 23.238 3.8246 23.9173.7175 25.439 3.4985 26.039 3.4193

Summary. Compound A freebase was identified as an amorphous solid formwith <0.5% weight loss before decomposition and a melting point of about87° C. It's hygroscopicity at 95% RH was <1% and had an epimer contentof <1l %. It's solubility at 37° C. was about 6.6 mg/mL. The XRPDpattern for the amorphous form is provided in FIG. 33. Compound C Form 1was a crystalline solid with <0.5% weight loss before decomposition anda melting point of about 165-174° C. Multiple forms of Compound C wereobtained dependent upon the solvent. It's hygroscopicity at 95% RH was<1.5% and had an epimer content of <1%. It's solubility at 37° C. wasabout 6.6 mg/mL. The Compound B Form B was a crystalline solid with<0.5% weight loss before decomposition and a melting point of about 168°C. A single form was present in anhydrous Form B. It's hygroscopicity at95% RH was <1% and had an epimer content of <2.5%. It's solubility at37° C. was about 5.9 mg/mL. The anhydrous form of Compound B Form B wasfound to be a stable pure crystalline form with properties morefavorable than Forms D, E, and F as described herein.

Example 33

Evaluation of safety, pharmacokinetics, and activity of Compound B.Breast cancer is the most frequent cancer diagnosed in women, with anestimated global incidence of 1.67 million new cases reported in 2012(Ferlay et al. 2013). Breast cancer accounts for approximately 15%(approximately 522,000 cases) of all cancer deaths.

Approximately 80% of all breast cancers express the estrogen receptor(ER) factor, and the vast majority of these are dependent on ER fortumor growth and progression. Modulation of estrogen activity and/orsynthesis is the mainstay of therapeutic approaches in women withER-positive breast cancer. However, despite the effectiveness ofavailable endocrine therapies such as ER antagonists (e.g., tamoxifen),aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane) andfull ER antagonists/degraders (e.g., fulvestrant), many patientsultimately relapse or develop resistance to these agents and thereforerequire further treatment for optimal disease control.

Despite becoming refractory to aromatase inhibitors or tamoxifen, growthand survival of resistant tumor cells remain dependent on ER signaling;therefore, patients with ER-positive breast cancer can still respond tosecond- or third-line endocrine treatment after progression on priortherapy (Di Leo et al. 2010; Baselga et al. 2012). There is growingevidence that in the endocrine resistant state, ER can signal in aligand-independent manner via input from other signaling pathways(Miller et al. 2010; Van Tine et al. 2011). Without being bound by anyparticular theory, an agent with a dual mechanism of action (ERantagonism plus degradation) has the potential to target bothligand-dependent and ligand-independent ER signaling and, consequently,improve treatment outcomes in late-stage ER-positive breast cancer.Furthermore, recent studies have identified mutations in ESRI (i.e., thegene that encodes for ERa) affecting the ligand-binding domain (LBD) ofthe ER (Segal and Dowsett 2014). In nonclinical models, mutant ER candrive transcription and proliferation in the absence of estrogen,suggesting that LBD-mutant forms of ER may be involved in mediatingclinical resistance to some endocrine therapies (Li et al. 2013;Robinson et al. 2013; Toy et al. 2013). ER antagonists that areefficacious against these ligand-independent, constitutively-activeER-mutated receptors may possess substantial therapeutic benefit.

As such, there is a need for new ER-targeting therapies with increasedanti-tumor activity to further delay disease progression and/or overcomeresistance to the currently available endocrine therapies and ultimatelyprolong survival in women with ER-positive breast cancer.

Compound B is a potent, orally bioavailable, small-molecule therapeuticagent that is being developed for the treatment of patients withER-positive breast cancer. As provided herein Compound B, including itssolid forms (e.g. Form B) are stable compounds with favorable propertiesfor continued pharmaceutical development. Without being bound by anyparticular theory, Compound B appears to antagonize the effects ofestrogens via competitive binding to the LBD of both wild-type andmutant ER with nanomolar potency. Upon binding, and without being boundby any particular theory, Compound B induces an inactive conformation tothe ER LBD, as measured by displacement of co-activator peptides. Inaddition to its direct antagonist properties, without being bound by anyparticular theory, the mechanism of action of Compound B includesreducing levels of ERa protein through proteasome-mediated degradation.Degradation of ER is hypothesized to enable full suppression of ERsignaling, which is not achieved by first-generation ER therapeuticssuch as tamoxifen, which display partial agonism. Compound B potentlyinhibits the proliferation of multiple ER-positive breast cancer celllines in vitro, including cells engineered to express clinicallyrelevant mutations in ER.

In vivo, Compound B exhibited dose-dependent anti-tumor activity inxenograft models of ER-positive breast cancer, including in apatient-derived xenograft model that harbors an ESRI mutation(ER.Y537S). The efficacious dose range was found to be 0.1-10 mg/kg/day,and all doses were well tolerated. Fulvestrant, when dosed according toa clinically relevant dosing scheme, was less efficacious than CompoundB in the assessed xenograft models. Thus, Compound B demonstrated robustnonclinical activity in ER-positive breast cancer models ofESR1-wildtype- and ESR1-mutation-bearing disease.

Example 34

In vitro and in vivo efficacy analysis of Compound B. Compound Bdisplays superior ER degradation & ER pathway suppression when comparedto both GDC-0927 GDC-0810. Further, Compound B has better DMPKproperties than both GDC-0927 and GDC-0810—resulting in same in vivoefficacy as GDC-0927 but at 100× lower doses (e.g. 1 mg or 10 mg dose).(See FIG. 34 and FIG. 35).

Pharmacokinetics and Metabolism. After a single IV administration torats, dogs, and monkeys, Compound B was found to have a low to moderateclearance, a large volume of distribution, and a terminal eliminationhalf-life of 7-24 hours. Oral bioavailability was moderate in rats anddogs (41%-55%) and low (17%) in monkeys. In vitro data showed thatplasma protein binding of Compound B was high across all species,ranging from 98% to 99% bound.

In vitro metabolite identification experiments showed thatUGT1A4-mediated glucuronidation was the major in vitro metabolic pathwayof Compound B. The contribution from CYP450 isoforms was minor andincluded both CYP3A4 and CYP2C9. In vitro CYP inhibition studies inhuman liver microsomes and induction studies in human hepatocytessuggested a low-to-moderate potential for drug-drug interactions.Compound B directly inhibited CYP3A4 with 50% inhibitory concentration(IC₅₀) values of 6.5 μM (midazolam 1′-hydroxylation) and 26 μM(testosterone 6p-hydroxylation); IC₅₀ for CYP2B6 and CYP2C8 inhibitionwere 13 μM and 21 μM, respectively. Compound B showed weak metabolismdependent inhibition of CYP2C9.

Toxicology. Four-week Good Laboratory Practice (GLP) repeat-dose oraltoxicity studies in female rats and monkeys with integrated assessmentsof neurologic (rats, monkey), respiratory (monkey), and cardiovascular(monkey) function were conducted to characterize the nonclinical safetyprofile of Compound B.

In the rat study, Compound B was tolerated at the exemplary dose levels(10, 30, and 100 mg/kg) with adverse effects predominantly in thekidneys and liver at 100 mg/kg. In the monkey study (20, 60, and 200mg/kg), the maximum tolerated dose (MTD) was considered to be 60 mg/kgas the high dose of 200 mg/kg was not tolerated. Adverse effects wereprimarily observed at the high dose level of 200 mg/kg, and lack oftolerability was attributed to kidney and liver injury and inanition.

In both rats and monkeys, there was a dose-dependent PLD observed innumerous organs at exposures that were higher than those anticipated atthe human starting dose in Phase I (at least 44-fold and 6-fold based onarea under the concentration-time curve [AUC], respectively), withadverse organ effects largely confined to the kidney and liver. In rats,PLD was not noted at 10 mg/kg (18-fold exposure factor), but increasedin incidence and severity from 30 to 100 mg/kg. In monkeys,dose-responsive PLD was present at all doses but was limited to minimalchanges in the lung at 20 mg/kg (6-fold exposure factor). These exposuremultiples provide evidence that the risk of PLD-associated toxicity tohumans in the Phase I starting dose is low.

The translatability of PLD from nonclinical species to patients is notcertain but can be reasoned (Reasor et al. 2006). Drugs such astamoxifen and palbociclib have not demonstrated any clinical concerns inspite of their PLD findings in nonclinical studies. Although Compound Bwas associated with PLD in multiple tissues in both rats and monkeys,there was no light microscopic evidence of involvement of criticalorgans such as heart, eyes, or neurons in these studies (Chatman et al.2009).

Following 28-day oral administration to rats and monkeys, the increasesin systemic exposure of Compound B were dose proportional. Based on thenature and reversibility of clinical signs, clinical pathology, andhistopathology findings, the severely toxic dose for 10% of animals(STD₁₀) for rats was defined as 100 mg/kg, with corresponding maximumplasma concentration (C_(max)) and AUC from 0 to 24 hours (AUC₀₋₂₄)values of 6560 ng/mL and 143,000 ng*hr/mL, respectively. In monkeys, thehighest non-severely toxic dose was defined as 60 mg/kg/day, withcorresponding Cm_(ax) and AUC₀₋₂₄ values of 841 ng/mL and 16,200ng*hr/mL, respectively, due to the clinical signs and moribunditiespresent at 200 mg/kg/day.

In summary, results from the nonclinical toxicity and safetypharmacology studies completed to date provide a robust characterizationof the toxicity profile of Compound B and support administration tocancer patients in a Phase I trial.

Administration of Compound B as a Single Agent Monotherapy. Compound Bdemonstrated robust nonclinical activity in ER-positive breast cancermodels of ESR1-wildtype and ESR1-mutation bearing disease. The safety,pharmacokinetic (PK), pharmacodynamic (PD) activity and preliminaryanti-tumor activity of Compound B as a single agent was analyzed in aPhase Ia/Ib, multicenter, open-label study in patients with locallyadvanced or metastatic ER-positive breast cancer. Patients were enrolledin a dose-escalation stage with enrollment in an expansion stage tofollow. During the single-agent dose escalation, cohorts were evaluatedat escalating dose levels to determine the MTD or maximum administereddose (MAD).

Once the single-agent MTD or MAD has been established, an escalationcohort treated with Compound B (at or below the MTD or MAD) or CompoundB in combination with palbociclib may be enrolled. Additionally,patients will be enrolled in the expansion stage and treated at or belowthe single-agent MTD or MAD of Compound B alone or in combination withpalbociclib and/or

TABLE 38 Patient response to treatment with Compound B: Cohort Patient(Dose) Days (status) BL disease (SLD) Response C3 3 (90 mg)  15 (active)Bone-only (NM) NA C2 3 (90 mg)  36 (active) Lung, liver, LN, bone (>100mm) NA C1 3 (90 mg)  57 (active) Bone-only (NM) NA B6 2-BF (30 mg)     2(active) LN, Bone (87 mm) NA B5 2-BF (30 mg)     28 (active) LN, Bone(35 mm) NA B4 2-BF (30 mg)     29 (active) Bone only (NM) NA B3 2 (30mg)  62 (PD) Liver (30 mm) PD B2 2 (30 mg) 119 (active) Pulm/hilar (38mm) SD (−9%) B1 2 (30 mg) 127 (active) Bone-only (NM) SD (NM) A6 1-BF(10 mg)     64 (Clinical PD) Liver, LN, Bone (62 mm) SD (NM) A5 1-BF (10mg)     21 (Clinical PD) Liver, LN, Bone (13 mm) cPD A4 1-BF (10 mg)    45 (Clinical PD) Bone-only (NM) cPD A3 1 (10 mg) 183 (active) Breast(50 mm) uPR (−40%) A2 1 (10 mg) 183 (active) Pulmonary (36 mm) SD (−27%)A1 1 (10 mg)  64 (PD) Bone-only (NM) PD

One treated patient was diagnosed with ER+PR+ breast cancer. The patienthad undergone previous surgery and previous treatment with anti-canceragents, including SERM therapy and AM therapy prior to enrollment andtreatment. The patient was treated with Compound B at 10 mg and showedresponse to the treatment after 3 cycles as indicated in FIG. 36a andFIG. 36 b.

Another patient was diagnosed with early stage HR+ breast cancer and hadreceived prior surgery and treatment with anti-cancer agents, includticethe invention, CDK4/6 ing makhibitors, and s. The patient was treatedwith Compound B at 10 mg and showed response to the treatment after 3cycles as indicated in FIG. 37a and FIG. 37b . was enrolled on our trialat 10 mg in March 2018.

The treated patients to-date demonstrate that administration of CompoundB is well-tolerated at 10 mg and 30 mg, with only Grade 1 and 2 AEs. Ingeneral, plasma exposures of Compound B increased proportionally withdoses from 10 to 30 mg after single dose. The steady state exposuresappeared to increase in a higher than dose proportional manner from 10mg to 30 mg. The estimated half-life of about 40 hours supportsonce-daily dosing.

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any devices orsystems and performing any incorporated methods. The patentable scope ofthe invention is defined by the claims, and may include other examplesthat occur to those skilled in the art. Such other examples are intendedto be within the scope of the claims if they have structural elementsthat do not differ from the literal language of the claims, or if theyinclude equivalent structural elements with insubstantial differencesfrom the literal languages of the claims.

1. A compound having the structure:


2. A crystal form comprising Compound B

having an X-ray powder diffraction pattern comprising peaks at 19.32,20.26, 21.63, 23.28, or 24.81±0.1° 2θ (±0.1° 2θ).
 3. The crystal form ofclaim 2, wherein the crystal form of Compound B has an X-ray powderdiffraction pattern one, two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, or twenty, characteristic X-ray powderdiffraction peaks as set forth in Table
 16. 4.-6. (canceled)
 7. Acrystal form comprising Compound B

having an X-ray powder diffraction pattern comprising peaks at 11.49,12.54, 19.16, 19.42, or 24.67±0.1° 2θ(±0.1° 2θ).
 8. The crystal form ofclaim 7, wherein the crystal form of Compound B has an X-ray powderdiffraction pattern one, two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, or twenty, characteristic X-ray powderdiffraction peaks as set forth in Table
 11. 9.-11. (canceled)
 12. Acrystal form comprising Compound B

having an X-ray powder diffraction pattern substantially as shown inFIG.
 10. 13. A crystal form comprising Compound B

having an X-ray powder diffraction pattern comprising peaks at 11.31,15.70, 16.54, 19.10, or 22.76±0.1° 2θ.
 14. The crystal form of claim 13,wherein the crystal form of Compound B has an X-ray powder diffractionpattern one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, or twenty, characteristic X-ray powder diffractionpeaks as set forth in Table
 13. 15.-17. (canceled)
 18. A crystal formcomprising Compound B

having an X-ray powder diffraction pattern substantially as shown inFIG.
 14. 19. A crystal form comprising Compound B

having an X-ray powder diffraction pattern comprising peaks at 12.52,15.90, 19.66, 20.65, or 24.99±0.1° 2θ.
 20. The crystal form of claim 19,wherein the crystal form of Compound B has an X-ray powder diffractionpattern one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, or twenty, characteristic X-ray powder diffractionpeaks as set forth in Table
 14. 21.-23. (canceled)
 24. A crystal formcomprising Compound B

having an X-ray powder diffraction pattern comprising peaks at 11.46,12.51, 19.29, 19.42, or 20.23±0.1° 2θ.
 25. The crystal form of claim 24,wherein the crystal form of Compound B has an X-ray powder diffractionpattern one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, or twenty, characteristic X-ray powder diffractionpeaks as set forth in Table
 15. 26.-27. (canceled)
 28. A crystal formcomprising Compound C

having an X-ray powder diffraction pattern comprising peaks at 16.09,18.92, 19.69, 19.86, or 23.16±0.1° 2θθ.
 29. The crystal form of claim28, wherein the crystal form of Compound C has an X-ray powderdiffraction pattern one, two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, or twenty, characteristic X-ray powderdiffraction peaks as set forth in Table
 30. 30. (canceled)
 31. Anamorphous solid comprising Compound A

32.-33. (canceled)
 34. A pharmaceutical composition comprising thecompound of claim 1 and at least one pharmaceutically acceptableexcipient.
 35. A method for treating lung cancer, ovarian cancer,endometrial cancer, prostate cancer, uterine cancer, or breast cancer ina patient having said cancer, said method comprising administering aneffective amount of the compound of claim 1 to the cancer patient.
 36. Amethod for treating breast cancer in a breast cancer patient, saidmethod comprising administering an effective amount of the compound ofclaim 1 to the cancer patient.
 37. The method of claim 36, wherein saidbreast cancer is hormone receptor positive breast cancer, HER2-positivebreast cancer, triple negative breast cancer,
 38. The method of claim36, wherein the breast cancer is metastatic breast cancer. 39.-41.(canceled)
 42. The method of claim 37, wherein the hormone receptorpositive breast cancer is HER2 negative.
 43. The method of claim 36,wherein the patient has had previous treatment with one or moreanti-cancer agents or radiation therapy.
 44. (canceled)
 45. The methodof claim 36, wherein the compound is administered in combination withone or more of radiation therapy, hormone therapy, or an anti-canceragent. 46.-47. (canceled)
 48. The method of claim 45, wherein theanti-cancer agent is abemaciclib, ribociclib, or palbociclib.
 49. Themethod of claim 45, wherein the anti-cancer agent is ipatasertib.50.-53. (canceled)
 54. A process for preparing a compound of formula(IV) or a salt thereof, the process comprising: (a) reacting a reactionmixture comprising a compound of formula (I), an organic solvent andthionyl chloride to form a compound of formula (IIa) according to step 1below, and reacting a reaction mixture comprising the compound offormula (IIa), a catalyst, an oxidant and a solvent to form a compoundof formula (II) according to step 2 below

wherein each of R^(1a) and R^(1b) is independently hydrogen, halogen,C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, —CN, C₃₋₆ cycloalkyl, or C₃₋₆spirocycloalkyl, and n is an integer of 2 or 3; and (b) reacting areaction mixture comprising the compound of formula (II) and a compoundof formula (III) in an organic solvent to form a compound of formula(IV) or a salt thereof according to step 3 below

wherein B is substituted or unsubstituted indolyl, benzofuranyl,benzothiophenyl, indazolyl, aza-indolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl, each of R^(2a) and R^(2b) is independently hydrogen,halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, or C₃₋₆ spirocycloalkyl, R^(3a) andR^(3b) are independently hydrogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl, C₃₋₆heteroaryl, or C₃₋₆ spirocycloalkyl, and the asterisk represents achiral center when R^(3a) and R^(3b) are different.
 55. The process ofclaim 54, wherein B is a substituted or unsubstituted indolyl,benzofuranyl, or benzothiophenyl.
 56. The process of claim 55, wherein Bis a substituted or unsubstituted indolyl.
 57. The process of claim 54,wherein B is a substituted or unsubstituted pyrrolopyridazinyl,pyrrolopyrimidinyl, or pyrrolopyrazinyl.
 58. The process of claim 54,wherein B is substituted with one or two substituents independentlyfluorine, chlorine, C₁₋₃ alkyl, C₁₋₃ haloalkyl, —CN, —OH, C₁₋₃ alkoxy,or C₁₋₃ hydroxyalkyl.
 59. The process of claim 54, wherein each ofR^(1a) and R^(1b) is independently hydrogen, F, —Cl, —OH, —CN, —CH₃,—CF₃, —CHF₂, —CH₂F, or spirocyclopropyl.
 60. The process of claim 54,wherein n is
 3. 61. The process of claim 54, wherein:

is of the formula


62. The process of claim 54, wherein each of R^(2a) and R^(2b) ishydrogen.
 63. The process of claim 54, wherein R^(3a) and R^(3b) areindependently hydrogen or —CH₃.
 64. The process of claim 54, wherein thestep 1 and step 2 organic solvent is a non-polar solvent.
 65. Theprocess of claim 54, wherein the step 2 catalyst is redox active metalcatalyst.
 66. The process of claim 54, wherein the step 3 organicsolvent is a polar aprotic solvent.
 67. The process of claim 54, whereinstep 3 further comprises an acid catalyst.
 68. The process of claim 54,wherein the compound of formula (I) is:

including stereoisomers thereof.
 69. The process of claim 54, whereinthe compound of formula (II) is:

including stereoisomers thereof.
 70. The process of claim 54, whereinthe compound of formula (III) is:

wherein X is —NH—, —N—C₁-C₃ unsubstituted alkyl, —O— or —S—.
 71. Theprocess of claim 70, wherein the compound of formula (III) is:


72. The process of claim 54, wherein the compound of formula (IV) is:

salt thereof, including stereoisomers thereof.
 73. The process of claim54, wherein: the compound of formula (I) is

the compound of formula (II) is

the compound of formula (III) is

the compound of formula (IV) is


74. A process for preparing a compound of formula (VIII) or a saltthereof, the process comprising: (a) reacting a reaction mixturecomprising a compound of formula (IV), a compound of formula (V) or acompound of formula (X), and an organic solvent to form a compound offormula (VI) according to step 1 below

wherein B is substituted or unsubstituted indolyl, benzofuranyl,benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl; each of R^(1a) and R^(1b) is independently hydrogen,fluorine, chlorine, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃hydroxyalkyl, and —CN, C₃₋₆ cycloalkyl, or C₃₋₆ spirocycloalkyl, n is aninteger of 2 or 3, each of R^(2a) and R^(2b) is independently hydrogen,halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, or C₃₋₆ spirocycloalkyl, R^(3a) andR^(3b) are independently hydrogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, —CN, C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl, C₃₋₆heteroaryl, or C₃₋₆ spirocycloalkyl, J is phenyl or pyridinyl; each R⁴is independently hydrogen, halogen or C₁₋₃ alkyl, s is an integer from 0to 2, LG is a leaving group, LG and CHO are located in the para positionwith respect to each other on J on the compound of formula (V), PG is analdehyde protecting group, LG and CH-PG are located in the para positionwith respect to each other on J on the compound formula (X), and eachasterisk independently represents a chiral center wherein the carbonbearing R^(3a) and R^(3b) is a chiral center when R^(3a) and R^(3b) aredifferent; and (b) reacting a reaction mixture comprising the compoundof formula (VI), an organic solvent, and a compound of formula (VII) ora salt thereof to form a compound of formula (VIII) or a salt thereofaccording to step 2 below

wherein G is C₁₋₃ alkyl, p is 0 or 1, E is substituted or unsubstitutedazetidinyl or pyrrolidinyl, each R⁵ is independently hydrogen, halogen,—OH, —CN, C₁₋₅ alkoxy, or C₁₋₅ hydroxyalkyl, v is an integer from 1 to5, and R⁶ is halogen or —CN; R¹⁰ is hydrogen or C₁₋₃ alkyl. 75.-87.(canceled)
 88. The process of claim 74, wherein E is azetidinyl of thefollowing structure:

89.-96. (canceled)
 97. The process of claim 74, wherein the compound offormula (IV) is:

or salt thereof, including stereoisomers thereof.
 98. The process ofclaim 74, wherein the compound of formula (V) is:

or a salt thereof.
 99. The process of claim 74, wherein the compound offormula (X) is:


100. The process of claim 74, wherein the compound of formula (VI) is:

or a salt thereof, including stereoisomers thereof.
 101. The process ofclaim 74, wherein the compound of formula (VII) is:

or a salt thereof.
 102. The process of claim 74, wherein the compound offormula (VIII) is:

or a pharmaceutically acceptable salt thereof including stereoisomersthereof.
 103. (canceled)
 104. The process of claim 74, wherein thecompound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof.
 105. The process of claim104, wherein the compound of formula (VIII) is:


106. (canceled)
 107. A process for preparing a compound of formula(VIII) or a salt thereof, the process comprising reacting a reactionmixture comprising a compound of formula (IX) or a compound of formula(XI), a compound of formula (IV) and an organic solvent to form thecompound of formula (VIII) or a salt thereof according to step 1 below

wherein: B is substituted or unsubstituted indolyl, benzofuranyl,benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, orfuropyrazinyl; each of R^(1a) and R^(1b) is independently hydrogen,halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃hydroxyalkyl, and —CN, C₃₋₆ cycloalkyl, or C₃₋₆ spirocycloalkyl; n is aninteger of 2 or 3; each of R^(2a) and R^(2b) is independently hydrogen,halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, or C₃₋₆ spirocycloalkyl; R^(3a) andR^(3b) are independently hydrogen, halogen, —OH, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, or C₃₋₆spirocycloalkyl; J is phenyl or pyridinyl; each R⁴ is independentlyhydrogen, halogen or C₁₋₃ alkyl; s is an integer from 0 to 2; G is C₁₋₃alkyl; p is 0 or 1; E is substituted or unsubstituted azetidinyl orpyrrolidinyl; each R⁵ is independently hydrogen, halogen, —OH, —CN, C₁₋₅alkoxy or C₁₋₅ hydroxyalkyl; v is an integer from 1 to 5; R⁶ is halogenor —CN; R¹⁰ is H or C₁₋₃ alkyl; the CHO moiety and the nitrogen atomlinking J and G are located in the para position with respect to eachother on J on the compound of formula (IX); PG is an aldehyde protectinggroup, CH-PG and the nitrogen atom linking J and G are located in thepara position with respect to each other on J on the compound of formula(XI); and each asterisk independently represents a chiral center whereinthe carbon bearing R^(3a) and R^(3b) is a chiral center when R^(3a) andR^(3b) are different. 108.-117. (canceled)
 118. The process of claim107, wherein E is azetidinyl of the following structure:

119.-125. (canceled)
 126. The process of claim 107, wherein the compoundof formula (IV) is:

or salt thereof, including stereoisomers thereof.
 127. The process ofclaim 107, wherein the compound of formula (IX) is:

or a salt thereof.
 128. The process of claim 107, wherein the compoundof formula (XI) is:

or a salt thereof.
 129. The process of claim 107, wherein the compoundof formula (VIII) is:

or a pharmaceutically acceptable salt thereof including stereoisomersthereof.
 130. (canceled)
 131. The process of claim 107, wherein thecompound of formula (VIII) is:

or a pharmaceutically acceptable salt thereof.
 132. The process of claim131, wherein the compound of formula (VIII) is:


133. (canceled)
 134. A process for preparing a compound of formula (IX)or a salt thereof, the process comprising: (1) reacting a reactionmixture comprising a compound of formula (X), a compound of formula(VII) or a salt thereof, an organic solvent and a catalyst to form acompound of formula (XI) according to step 1 below

wherein J is phenyl or pyridinyl; each R⁴ is independently hydrogen,halogen or C₁₋₃ alkyl, s is an integer from 0 to 2, LG is a leavinggroup, PG is an aldehyde protecting group, LG and CH-PG are located inthe para position with respect to each other on J, G is C₁₋₃ alkyl, p is0 or 1, E is substituted or unsubstituted azetidinyl or pyrrolidinyl,each R⁵ is independently hydrogen, halogen, —OH, —CN, C₁₋₅ alkoxy orC₁₋₅ hydroxyalkyl, v is an integer from 1 to 5, R⁶ is halogen or —CN,and R¹⁰ is hydrogen or C₁-C₃ alkyl; and (2) deprotecting the compound offormula (XI) to form the compound of formula (IX) according to step 2below

135.-139. (canceled)
 140. The process of claim 134, wherein E isazetidinyl of the following structure:

141.-149. (canceled)
 150. The process of claim 134, wherein the compoundof formula (IX) is:

or a salt thereof.
 151. A process for preparing a compound of formula(III) or a salt thereof, the process comprising: (1) reacting a reactionmixture comprising a compound of formula (XII), a compound B and anorganic solvent to form the compound of formula (XIII) according to step1 below

wherein: B is selected from substituted or unsubstituted indolyl,benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl,pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl,thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl,and furopyrazinyl, each of R^(2a) and R^(2b) is independently selectedfrom hydrogen, halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, and C₃₋₆ spirocycloalkyl,R^(3a) and R^(3b) are independently selected from hydrogen, halogen,—OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, —CN,C₃₋₆ cycloalkyl, and C₃₋₆ spirocycloalkyl, PG is an amine protectinggroup, and each asterisk represents a chiral center when R^(3a) andR^(3b) are different; and (2) deprotecting the compound of formula(XIII) to form the compound of formula (III) according to step 2 below

152.-159. (canceled)
 160. The process of claim 151, further comprisingpreparing the compound of formula (XII) or a salt thereof, the processcomprising: (1) reacting a reaction mixture comprising a compound offormula (XIV), thionyl chloride, and an organic solvent to form acompound of formula (XV) according to step 3a below

and (2) reacting a reaction mixture comprising the compound of formula(XV), a catalyst, an oxidizing agent, and an organic solvent to form thecompound of formula (XII) according to step 3a below

161.-162. (canceled)
 163. A compound of formula (XVI)

wherein: each R⁴ is independently selected from hydrogen, halogen andC₁₋₃ alkyl; s is an integer from 0 to 2; G is C₁₋₃ alkyl; p is 0 or 1;each R^(7a) and R^(7b) is independently selected from hydrogen, halogen,C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ hydroxyalkyl, and —CN; each R^(8a) andR^(8b) is independently selected from hydrogen, halogen, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ hydroxyalkyl, and —CN; R¹⁰ is hydrogen or C₁₋₃alkyl; y is an integer selected from 1 and 2, x is an integer selectedfrom 1 and 2, and the total of x and y is 2 or 3; M is substituted orunsubstituted C₁₋₅ alkyl; r is 0 or 1; and R⁹ is halogen or —CN.164.-170. (canceled)
 171. The compound of claim 163, wherein compoundformula (XVI) is selected from:

or a salt thereof.
 172. A process for preparing a compound havingformula (XX):

the process comprising: contacting a compound of formula (XXI)

with a protein transaminase to form a compound of formula (3):

contacting the compound of formula (3) with a compound of formula (II)to form compound formula (XX)

wherein n is 3; and each of R^(1a) and R^(1b) is independently selectedfrom hydrogen, halogen, —OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ hydroxyalkyl, —CN, C₃₋₆ cycloalkyl, and C₃₋₆ spirocycloalkyl. 173.The process of claim 172, wherein the protein transaminase is selectedfrom a (S)-enantioselective transaminase of SEQ ID NO:1, SEQ ID NO:2,SEQ ID NO:3, and SEQ ID NO:4.
 174. The process of claim 172, whereincompound formula (XX) is of the structure:

175.-179. (canceled)